Natural Cure for Hypertension

High Blood Pressure Exercise Program

The exercises in Three Easy Exercises to Drop Blood Pressure Below 120/80 take about 30 minutes a day, and you can do them while you're doing routine household chores. Christian Goodman is the researcher behind the Blue Heron Health High Blood Pressure Exercise Program. The creator has used these exercises effectively on himself, and he has tweaked them to make them as effective as possible. He personally used them for two weeks straight and lowered his own blood pressure drastically. For the next few weeks, he noticed that his blood pressure when up and down a little, but it never went back to as high as it was, and now he is sharing this method to reduce high blood pressure with confidence through Blue Heron. If you have high blood pressure, then this blood pressure program is worth a try. It is either that, or continue to take medication and suffer the effects of high blood pressure. With an 8-week, full money back guarantee, you have nothing to lose but your high blood pressure! Continue reading...

High Blood Pressure Exercise Program Summary


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Pulmonary Arterial Hypertension

SILDENAFIL (Revatio) Pulmonary arterial hypertension 20 mg PO tid. Contraindicated with nitrates. Coadministration is not recommended with ritonavir, potent CYP3A inhibitors, or other phosphodiesterase-5 inhibitors. Teach patients to seek medical attention for vision loss, hearing loss, or erections lasting longer than 4 h. Trade only (Revatio) Tabs 20 mg. LK 2B TADALAFIL (Adcirca) Pulmonary arterial hypertension 40 mg PO daily. Contraindicated with nitrates. Coadministration is not recommended with potent CYP3A inhibitors (itraconazole, ketoconazole), potent CYP3A inducers (rifampin), other phosphodiesterase-5 inhibitors. Caution with ritonavir, see PI for specific dose adjustments. Teach patients to seek medical attention for vision loss, hearing loss, or erections lasting longer than 4 h. Trade only (Adcirca) Tabs 20 mg. L 2B

Monooxygenase products in animal models of renal hypertension

In most cases, investigation of the biological effects of arachidonic acid monooxygenase products still remains somewhat fragmentary and descriptive. The relevant contribution of P-450 metabolites to renal physiology became clearer upon investigation of animal models of renal hypertension. A role for the kidney microsomal arachidonic acid monooxygenases in the development of hypertension in spontaneously hypertensive rats (SHRs) was first put forward by McGiff and coworkers in 1988 and has been confirmed in many studies since then (summarized in McGiff 145 ). SHRs develop hypertension between the ages of 5 and 13 weeks the vascular tone in the pre-glomerular vasculature of these animals is elevated. During this phase, an increase in -hydroxylase activity and protein was observed resulting in elevated production of 20-HETE 139 . Treatment of young rats with SnCl2 or hemarginate, which induce heme oxygenase and cause depletion of renal cytochrome P-450, reduced renal cortical microsomal...

CoQ10 in hypertension

The role of CoQ10 in decreasing blood pressure has been known since 1972. Yamagami et al. (1977) found low CoQ10 status in 29 patients with hypertension and treatment with CoQ10 (1-2 mg kg-1 day-1) caused a decrease in blood pressure. In a pilot study they administered 30-45 mg day-1 of CoQ10 to 17 patients with hypertension for 2-16 weeks (Yamagami et al., 1977). This produced a beneficial effect in only four patients. In another study by Yamagami et al. (1986), 20 patients having low serum CoQ10 levels were administered either 100 mg CoQ10 or placebo for 12 weeks. Treatment with CoQ10 was associated with a significant decrease in blood pressure. Montaldo et al. (1991) administered CoQ10, 100 mg day-1 for 3 months, to 15 patients with hypertension. There was a significant reduction in blood pressure, both at rest and during exercise, together with a significant improvement in myocardial stroke work index. Digiesi et al. (1994) also studied the role of CoQ10 in hypertension and...

Pregnancyinduced hypertension and preeclampsia

Pregnancy-induced hypertension (PIH) and pre-eclampsia are potentially severe complications of human gestation, occurring in approximately 5 of pregnancies. The clinical symptoms are hypertension, proteinurea and edema, which may be accompanied by growth retardation of the fetus. In advanced stages of the disease the patients also show cerebral symptoms, ranging from hyper-reflexia and headaches to general fits. Further, there is increased platelet activation leading to thrombopenia. Recent theories suggest that the beginning of the disease lies in a pathologically poor invasion of fetal trophoblast cells into the uterine arteries 129 . This is followed by a decreased blood supply to the placenta which then probably causes the general vasoconstriction in order to increase the placental perfusion. During the course of the disease a dysfunction of endothelial cells develops, resulting in a disorder of platelet-vessel-wall interaction which can explain many of the typical clinical...

A jAdrenoceptor Antagonists as Antihypertensive Drugs

In view of the role that the sympathetic nervous system plays in the control of vascular resistance, and the fact that a-adrenoceptors mediate the pressor effects of neuronally released norepinephrine as well as circulating epinephrine, it is logical that a-adrenoceptor antagonists were among the first pharmacological classes to be evaluated as antihypertensive drugs. However, the initial clinical investigations of the a-adrenoceptor antagonists then available, phenoxybenzamine and phentolamine, yielded disappointing results (2,3). Little reduction of supine blood pressure was produced and tolerance appeared to develop rapidly the side effects, such as orthostatic hypotension, were often intolerable. Clinical evaluation of prazosin in hypertensive patients showed the drug to be a highly effective antihypertensive agent, with sustained reductions observed in both standing and supine blood pressure (4). Other quinazolines, such as terazosin and doxazosin, provide a similar degree of...

A2Adrenoceptor Agonists as Antihypertensive Drugs

The use of a2-adrenoceptor agonists as centrally acting antihypertensive agents is based on the discovery, 30 years ago, of the hypotensive and bradycardic actions of clonidine (7). Clonidine was originally synthesized as an aradrenoceptor agonist to be used as a nasal decongestant, but clinical evaluation soon showed the drug to possess a different pharmacological profile from other imidazolines that were known at the time, which when administered systemically produced the anticipated increases in blood pressure. The mechanism responsible for the hypotensive action of clonidine was not clarified until a decade later when the subclassification of a-adrenoceptors into the ar and a2-adrenoceptor subtypes was established It is now firmly established that activation of postsynaptic a2-adrenoceptors in the brainstem by clonidine and clonidine-like drugs inhibits sympathetic outflow from the central nervous system and thereby lowers blood pressure and heart rate (11). Because the activation...

Effects of tea on hypertension

Hypertension is the most common form of CVD, affecting approximately 20 of the adult population in many countries.14 It is also one of the major risk factors for cardiovascular mortality, which accounts for 20-50 of all deaths. Some of the evidence was reviewed in 200414 and an association was suggested between tea drinking and a reduction in blood pressure in a Chinese population. These variable results have caused some confusion over the possible antihypertensive effect of green and black teas. Further epidemiological work was initiated in 1996, involving the participation of Chinese adult habitual tea drinkers in Taiwan.14 The long-term effects of tea drinking and various lifestyle and dietary factors were evaluated for the risk of developing hypertension.14 An inverse relationship was found between consumption of tea and mean blood pressure of individuals. Participants who had consumed at least 120 mL of tea per day for one year had a 46 lower risk of being diagnosed with...

Hypertension and heart failure

Hypertension Lowering raised blood pressure decreases the risk of stroke, coronary events, heart failure, and renal impairment. Advice on antihyper-tensive therapy in this section takes into account the recommendations of the Joint British Societies (JBS2 British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005 91 (Suppl V) v1-v52). Possible causes of hypertension (e.g. renal disease, endocrine causes), contributory factors, risk factors, and the presence of any complications of hypertension, such as left ventricular hypertrophy, should be established. Patients should be given advice on lifestyle changes to reduce blood pressure or cardiovascular risk these include smoking cessation, weight reduction, reduction of excessive intake of alcohol, reduction of dietary salt, reduction of total and saturated fat, increasing exercise, and increasing fruit and vegetable intake. Severe hypertension with acute target-organ damage, or severe...

Centrally acting antihypertensive drugs

Methyldopa is a centrally acting antihypertensive it may be used for the management of hypertension in pregnancy. Side-effects are minimised if the daily dose is kept below 1 g. Clonidine has the disadvantage that sudden withdrawal of treatment may cause severe rebound hypertension. Moxonidine, a centrally acting drug, is licensed for mild to moderate essential hypertension. It may have a role when thiazides, calcium-channel blockers, ACE inhibitors, and beta-blockers are not appropriate or have failed to control blood pressure.

Antihypertensive and antihypercholesterolemic activities

Angiotensin-I-converting enzyme (ACE) plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Further, ACE is implicated in cell oxidative stress, augmenting the generation of ROS and peroxynitrite and also in thrombosis, during which induces platelet activation, aggregation, and adhesion (McFarlane et al., 2003). Inhibition of ACE is considered to be a useful therapeutic approach in the treatment of hypertension. Therefore, in the development of drugs to control high blood pressure, ACE inhibition has become an important activity. Many studies have been attempted in the synthesis of ACE inhibitors such as captopril, enalapril, alcacepril, and lisinopril, which are currently used in the treatment of hypertension and heart failure in human. However, these synthetic drugs

Selection Of Antihypertensive Drugs In Individual Patients

Choice of an antihypertensive drug should be driven by likely benefit in an individual patient, taking into account concomitant diseases such as diabetes mellitus, problematic adverse effects of specific drugs, and cost. Consensus guidelines recommend diuretics as preferred initial therapy for most patients with uncomplicated stage 1 hypertension who are unresponsive to nonpharmacological measures. Patients are also commonly treated with other drugs p receptor antagonists, ACE inhibitors A receptor antagonists, and Ca2+ channel blockers. Patients with uncomplicated stage 2 hypertension will likely require the early introduction of a diuretic and another drug from a different class. Subsequently, doses can be titrated upward and additional drugs added in order to achieve goals (blood pressure 160 mm Hg and diastolic blood pressure

Gestational hypertension preeclampsia and eclampsia

Gestational hypertension is the most frequent cause of hypertension during pregnancy and the rate varies between 6 and 17 .14,15 Some women with gestational hypertension will subsequently progress to preeclampsia and the rate of progression depends on gestational age at the time of diagnosis. The rate reaches 50 when gestational hypertension develops before 30 weeks gestation. Preeclampsia is primarily defined as gestational hypertension plus proteinuria. Preeclampsia is considered severe if there is severe gestational hypertension in association with proteinuria (in the normal kidney, during the filtration process that takes place in the glomerulus, proteins do not enter the urinary space and the presence of proteins in urine is always a sign of glomerular disease) or in the presence of multiorgan involvement such as pulmonary edema (i.e. the passage of fluids from the pulmonar interstitial compartment to the alveolar lumen causing a severe obstacle to the diffusion of oxygen from...

Renal Parenchymal Disease and Hypertension

Summary This review article explores the interrelationship of renal parenchymal disease and hypertension. Topics include pathophysiology and pathogenesis sodium balance digitalis like factor (DLF) the renin angiotensin aldosterone system renal prostaglandins the renal kallikrein system endothelin (ET) endothelium derived relaxing factor nitric oxide (NO) nephron dosing, hypertension, and renal injury treatment considerations, including protein and sodium restriction, diuretics, and treatment for refractory hypertension and strategies to retard the progression of renal disease. The authors conclude that renal parenchymal hypertension constitutes a 'fascinating constellation' with numerous and diverse causes and an incompletely defined pathophysiology. 123 references.

O Antihypertensive Agents

Hypertension is a consequence of many diseases. Hemodynamically, blood pressure is a function of the amount of blood pumped by the heart and the ease with which the blood flows through the peripheral vasculature (i.e., resistance to blood flow by peripheral blood vessels). Diseases of components of the central and peripheral nervous systems, which regulate blood pressure and abnormalities of the hormonal system, and diseases of the kidney and peripheral vascular network, which affect blood volume, can create a hypertensive state in humans. Hypertension is generally defined as mild when the diastolic pressure is between 90 and 104 mm Hg, moderate when it is 105 to 114 mm Hg, and severe when it is above 115 mm Hg. It is estimated that about 15 of the adult population in the United States (about 40 million) are hypertensive. Primary (essential) hypertension is the most common form of hypertension. Although advances have been made in the identification and control of primary hypertension,...

Therapy Of Hypertension

Hypertension is the most common cardiovascular disease its prevalence increases with advancing age. Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. Hypertension is the principal cause of stroke, is a major risk factor for coronary artery disease and its complications, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aortic aneurysm. Hypertension is defined as a sustained increase in blood pressure 140 90 mm Hg, a criterion where risk of hypertension-related cardiovascular disease is high enough to merit medical attention. The risk of fatal and nonfatal cardiovascular disease in adults is lowest with systolic BP 210 and or diastolic 120 mm Hg), some patients develop fulminant arteriopathy characterized by endothelial injury and marked intimal proliferation, leading ultimately to arteriolar occlusion and the syndrome of immediately life-threatening hypertension. This is associated with...

The Treatment Of Hypertension

There are other approaches to the treatment of hypertension arising from the heart muscle having to pump too hard. The adrenergic receptors are associated with ligand-gated ion-channels. Opening these channels allows an influx of calcium ions into the cell. This leads to the formation of a complex between the calcium ion and an intracellular protein, calmodulin, which then initiates muscle contraction. Compounds that block the opening of these ion-channels can have a vaso-dilating effect and are then useful in the treatment of hypertension. A number of dihydropyridines introduced in the 1970s such as nifedipine 3.55, have this action. Although nifedipine can be made by the classical Hantzsch synthesis using 2-nitrobenzaldehyde, ethyl acetoacetate and ammonia, a cleaner product is obtained by a two-step reaction. 2-Nitrobenzaldehyde is condensed with one mole of ethyl acetoacetate to give the benzylidene derivative 3.56. Addition of the enamine, ethyl 3-aminocrotonate 3.57, then gives...


The regulation of cellular calcium metabolism is central to blood pressure homeostasis the higher the level of cytosolic free calcium, the greater the smooth muscle vasoconstrictor tone, the catecholamine secretion, the sympathetic nervous system activity, and thus blood pressure. An increase of cellular calcium, as part of the final common pathway leading to vascular smooth muscle contraction, may directly explain the increased peripheral resistance characteristic of essential hypertension. Animal, clinical and some epidemi-ological evidence suggests that high blood pressure is associated with abnormalities of calcium metabolism and secondary activation of the parathyroid gland.4,25 30 Hypertension The effect of calcium dietary modifications on blood pressure control has generated great controversy. There are considerable epidemiological and clinical trial data on the relationship between blood pressure levels and calcium intake.31 Epidemiologically, a consistent inverse relationship...


May and co-workers have developed a series of phenylaminoethylselenides (PAESe) 19 that have anti-hypertensive properties.105 107 PAESe's antihypertensive activities appear to result from inhibition of dopamine -mono-oxygenase (DBM).105 DBM catalyzes the conversion of dopamine to noradrenalin and is dependent on ascorbate for catalytic activity (Figure 17.6). PAESes inhibit DBM by depleting ascorbate in the vesicles of chromaffin cells. DBM oxidizes PAESe 19 to the selenium oxide 20 using reduced ascorbate as a co-factor. The reduced PAESe 19 is regenerated by reduced ascorbate.

Definitions And Applications

Finally, biomarkers represent clinical endpoints when they measure directly how a patient feels or functions. They may also measure survival. In those rare circumstances where a marker may actually be substituted for a clinical endpoint, they are called surrogate endpoints. They are used to predict clinical benefit, or safety, based on epidemiological, therapeutic, or pathophysiological evidence. The use of blood pressure (hypertension) as a surrogate for stroke, or measure of risk for that event, has become a classic and rare example of a true surrogate endpoint 5 .

Present Situation And Potential Of Seaweeds For Novel Functional Food Product Developments

Isotonic drinks, bakery, and hypoallergenic baby foods. Further, ever-concerning chronic disease-related conditions such as cancer, high cholesterol, coronary heart diseases, atherosclerosis, stroke, hypertension, diabetes (type II), gastrointestinal disorders, osteoporosis, intestinal complications, and immune disorders including allergy have been used as prime focuses when developing these functional food products. When analyzing the supply structure of these functional foods, the main types of successful actors in the commercial functional food segment are multinational food companies with a broad product range and pharmaceutical or dietary products producing companies. Therefore, the combination of consumer acceptance, advances in science and technology, and scientifically backed evidence linking consumption of biochemical compounds in seaweed to disease and disease prevention can be taken as unprecedented opportunity for these food marketers to develop seaweed-based functional...

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Stage 1 Lead Finding or Establishing Directions One to Two Years

It is not uncommon for large companies to suddenly establish a direction through serendipitous discoveries. Alexander Fleming discovered penicillin as a result of serendipity. Although many of the drugs that are in use today have been discovered in this way, it is a difficult route for the pharmaceutical industry to follow and breaks are few and far between. More recently, the discovery that the phosphodiesterase type 5 inhibitor (originally tested as antihypertensive agents) can be a good candidate for male erectile dysfunction has changed the focus of research at Pfizer, and as a result, at several other companies.

Identifying effective drug treatments

The prescribing notes in the BNF provide an overview of the drug management of common conditions and facilitate rapid appraisal of treatment options (e.g. hypertension, p. 104). For ease of use, information on the management of certain conditions has been tabulated (e.g. acute asthma, p. 173). Information is also provided on the prevention of disease (e.g. malaria prophylaxis for travellers, p. 404). Cardiovascular risk prediction charts for the primary prevention of cardiovascular disease can be found in the glossy pages at the back of the BNF.

Pharmacodynamic Interactions

Combinations of drugs often are employed to therapeutic advantage when their beneficial effects are additive or synergistic or because therapeutic effects can be achieved with fewer drug-specific adverse effects by using submaximal doses of drugs in concert. Combination therapy often constitutes optimal treatment for many conditions, including heart failure (see Chapter 33), hypertension (see Chapter 32), and cancer (see Chapter 51). This section addresses pharmacodynamic interactions that produce adverse effects. A subset of nonsteroidal anti-inflammatory drugs, including indomethacin, ibuprofen, piroxi-cam, and the cyclooxygenase (COX)-2 inhibitors, can antagonize antihypertensive therapy, especially with regimens employing angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and b adrenergic receptor antagonists. The effect on arterial pressure ranges from trivial to severe. In contrast, aspirin and sulindac produce little, if any, elevation of blood pressure...

Reduction of lipid absorption and cardiovascular diseases

Reduction of the risk of cardiovascular diseases by consuming seaweed is suggested due to its modifying effects on the gastrointestinal tract such as emulsification of bile acid and interfering with lipid micelle formation, dilution of lipase concentration, binding with cholesterol, and slowing down of lipid absorption. Studies carried out using rats reported that alginic acid leads to a decrease in the concentration of cholesterol and is often coupled with an increase in the fecal cholesterol content and a hypocholesterolemic response (Dumelod et al., 1999). Moreover, porphyran significantly lowered the artificially enhanced level of hypertension and blood cholesterol in rats conserving cardiac health (Noda, 1993).

Impact of pain on quality of life

Estimates of the economic burden associated with pain fail to do justice to the extent of suffering and reduced quality of life experienced by patients and warrants pain relief being regarded as a universal human right.18 Chronic pain, along with musculoskeletal disorders, has been shown to be associated with some of the poorest quality-of-life states.60,61,62,63 In patients referred to a Danish multidisciplinary pain center, the severity of impairment was equal to or lower than patients with cardiopulmonary diseases and major depression, and their Psychological General Well-being Scale scores were lower than those with hypertension and gastrointestinal problems, while they also displayed high levels of anxiety and depression, as measured by the Hospital Anxiety and Depression Scale.63 In a study of over 600 patients attending a chronic pain clinic in Sydney, Australia, there were greatly reduced SF-36 domain scores between clinic patients and Australian norm values, as shown in Table...

Metabolic syndrome prevention

The WHO, in the 2009 report, states that high BP ranked first in the list of leading global risks for mortality and accounted for 7.5 million deaths in the world in 2004. According to MetS concept, elevated BP is clustered with other symptoms, including obesity, dyslipidemia, and glucose dys-regulation. For treating these disorders, clinical guidelines such as the National High Blood Pressure Education Program recommend, among others, weight loss, dietary sodium reduction (no more than 2.4 g d), adequate potassium intake (more than 3.5 g d), and consumption of a diet rich in fruit and vegetables. In its initial stage, one of the major concerns is on preventing disease worsening, and shifting to more adequate foods is crucial. In this context, functional foods play a relevant role if they supply what is needed to comply with dietary guidelines. Undaria pinnatifida (wakame) is a very popular food in the Asiatic countries (Suetsuna et al., 2004). Wakame has a fiber content similar to...

An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

(9) hypertension (2) hypertension Cushing's disease, which is caused by tumor-induced overproduction of Cortisol in the adrenals and excessive circulating Cortisol, leads to obesity, high blood pressure, osteoporosis, muscle weakness and several other problems. In contrast, patients with Addison's disease, who have a deficiency of Cortisol, are both thin and non-diabetic.

Acute myocardial infarction

Interest in the therapeutic use of magnesium in patients with acute myocardial infarction comes from non-controlled studies carried out in Australia, Asia and Europe concerning a supposed decrease in arrhythmic events and an increase in survival in patients treated with magnesium.57,58 Epidemiological studies have also reported that the incidence of sudden death is greater in geographical areas characterized by soft water, which are relatively poor in calcium and magne-sium.59 An epidemiological perspective study has been carried out into the relation between plasma levels of magnesium and the incidence of coronary artery disease,60 and another study investigated the relationship between dietary magnesium and coronary artery disease.61 In the latter study, 13 922 middle-aged subjects were studied for a follow-up period of from 4 to 7 years. The risk of the onset of coronary artery disease was significantly higher in subjects with low plasma levels of magnesium and there was a...

Usual Predominance of Sympathetic or Parasympathetic Tone at Various Effector Sites and Consequences of Autonomic

However, a decrease may occur if the heart rate is high initially. In patients with normal cardiac function, these drugs may reduce cardiac output as a consequence of diminished venous return resulting from venous dilation and peripheral pooling of blood. In patients with cardiac failure, ganglionic blockade frequently results in increased cardiac output owing to a reduction in peripheral resistance. In hypertensive subjects, cardiac output, stroke volume, and left ventricular work are diminished.

Adverse Effects Precautions

The untoward effects of NE resemble those of Epi, although there typically is greater elevation of blood pressure with NE. Excessive doses cause severe hypertension. Care must be taken that necrosis and sloughing do not occur at the site of intravenous injection owing to extravasation of the drug. The infusion should be made high in the limb, preferably through a long plastic cannula extending centrally. Impaired circulation at injection sites, with or without extravasation of NE, may be relieved by infiltrating the area with phentolamine, an a receptor antagonist. Blood pressure must be determined frequently. Reduced blood flow to organs such as kidney and intestines is a constant danger with the use of NE.

Vitamin E Supplement

Hence, intervention trials to date do not support a regimen of high-dose vitamin E ingestion for reducing risk of cardiovascular and or cancer death in high-risk populations. Furthermore, there is some evidence indicating a potential adverse effect on risk for hemorrhagic stroke in users of vitamin E supplements. Hemorrhagic stroke is classified as subarachnoid hemorrhage or intracerebral hemorrhage, and the risk profiles of these two subtypes are distinct. Subarachnoid hemorrhage is typically caused by rupture of an arterial aneurysm and has been related to a smoking-induced elastase a-antitrypsin imbalance (17), whereas intracerebral hemorrhage may be related more to hypertension and necrosis of small arterioles (18). The number of cigarettes smoked increased the risk of subarachnoid hemorrhage but not intracerebral hemorrhage (18). In smokers, vitamin E supplementation raised the risk of fatal subarachnoid hemorrhage (+181 , P 0.005) but did not alter risk of fatal intracerebral...

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Recently, ephedra preparations have been sold with misleading names alluding to the drug ecstasy (MDMA) (Blumenthal and King 1997). Several deaths have resulted from cardiac toxicity because hypertension and cardiac arrhythmia are chief problems with higher doses of ephedrine. Use of ephedra is thus contraindicated in people with existing high blood pressure. Cases have been reported of intracerebral hemorrhage and vasculitis in association with ephedrine (Forman et al. 1989 Kaye and Fainstat 1987 Wooten et al. 1983). The risk of cerebral hemorrhage is even greater when combining ephedrine with other catecholamine stimulants such as the over-the-counter stimulant phenyl-propanolamine (Stoessl et al. 1985). Pseudoephedrine may be safer than ephedrine in some respects (Porta et al. 1986). In a large sample (n 100,000) of pseudoephedrine users, there were no reports of cerebrovascular disorders within 15 days after administration. The incidence of myocardial infarction, seizures, and...

Optimal Amount of Dietary Calcium Intake and Benefits of Calcium Supplementation

In the Stone Age the diet of human adults is estimated to have contained from 50 to 75mmol of Ca (2000-3000 mg) day, three to five times the median calcium intake of the present day in Western countries.7 As the human genetic make-up has not modified, our body needs remain suited to a much higher calcium intake than we currently consume. Although mammalian physiology contains mechanisms by which organisms can adjust to temporary environmental shortages, chronic calcium retention has a number of health consequences. A number of chronic diseases have been linked to a low dietary calcium intake, including bone fragility, high blood pressure and colon cancer in susceptible individuals.8 Recent studies have also linked weight control and regulation of body fat to an adequate dietary calcium intake. We present here evidence indicating that an optimal dietary calcium intake may prevent to some extent each of these multifactorial problems. Several studies have addressed the possible role of...

Functional diversity of G3 and Gy subunits

Reports on defects of Gp functions leading to genetic diseases are scarce. Polymorphism of the Gp3 gene has been detected with a C825T base substitution in some hypertensive patients, which results in an alternatively spliced Gp3 subunit losing 41 amino acids (Siffert et al. 1998). The deleted region corresponds to one of the seven WD repeats. The shortened Gp3 (named Gp3S) can still fold into a functional protein with six blades only. Gp3S promotes Gi-mediated Ca2+ signals in lymphoblasts and enhances Na+ H+ exchanger activity. Gp3S is subsequently correlated to lower renin and elevated diastolic blood pressure levels, obesity, type II diabetes (Siffert 2000), enhanced chemotaxis of human neutrophils in response to interleukin-8 (Virchow et al. 1999), elevated serum potassium and cholesterol levels (Ishikawa etal. 2000), and coronary artery vasoconstriction (Meirhaeghe etal. 2001).

Weight Control and Regulation of Body

Non-institutionalized population, have been recently re-evaluated. Data have suggested that after controlling for energy intake and physical activity, contrary to common thought, an adequate calcium intake may actually be associated with a reduced likelihood of being in the highest quartile for adiposity.57 Zemel et al. reported an almost 80 difference in obesity rates between those Americans in the lowest quartile of dietary calcium intake versus those in the highest quartile.57 Several studies have reported an impact of supplemental dietary calcium on weight loss and have suggested that diets low in calories but high in calcium may provide some better protection against obesity. Experimental data in animals and in humans have also suggested a possible role of dietary calcium in regulating body fat, and an increase in lipolysis with a high-calcium low-fat diet, consistent with an increase in energy metabolism.58 61 Data from six observational studies and three controlled trials in...

Hepatic Inflammation and Fibrosis

When fibrogenesis takes over, however, collagens type I and III which are normally concentrated in the portal tracts and around central veins, are deposited throughout the liver. Collagen IV and VI and other components of the extracellular matrix are also increasingly expressed. The normal liver only contains 1-2 connective tissue, but in patients with cirrhosis this can increase up to a maximum of 50 75 . The increased amount of extracellular matrix results in severe disruption of blood flow and impaired diffusion of solutes between PCs and plasma, which may have implications for drug targeting preparations to hepatic cells. Deposition of collagens in the space of Disse is also accompanied by the loss of fenestrations in SECs, which further impairs the movement of proteins between PCs and plasma. The subsequent resistance to portal flow induces portal hypertension and together with the reduced metabolic capacity of the liver this leads to four major...

Liver Cirrhosis Causes and Therapy

A promising new development in drug therapy is the endothelin-antagonists 87,88 . Though not yet clinically tested, these compounds show potential in the management of portal hypertension, a hallmark of cirrhosis. Again, uptake of these antagonists by other parts of the body hampers their applicability 89 , which might be circumvented by drug targeting.

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Ginkgo has a number of other hematologic effects. Acute administration of the ginkgo extract, Kaveri, does not alter blood pressure or heart rate in humans (Jung et al. 1990). Chronic treatment with ginkgo extract (120 mg day for 3 months) lowered diastolic blood pressure (Winther et al. 1998). However, no changes were seen at a higher dose (240 mg day for 3 months). Also unchanged by ginkgo are haematocrit, plasma viscosity, erythrocyte rigidity, thrombocyte and leukocyte count, and thrombocyte aggregation. However, ginkgo does reduce erythrocyte aggregation by 15.6 (Jung et al. 1990). Ginkgo reduces pulmonary hypertension induced by chronic isobaric hypoxia (Cheng et al. 1996). In human platelets, ginkgolides reduce phospholipase C activation and the mobilization and influx of Ca2+ (Simon et al. 1987). This action is not observed with thrombin, suggesting that ginkgolides act through the membrane receptor of PAF-acether. Ginkgolides also reduce thromboxane B2 levels (Becker et al....

Anatomical Considerations For Assessment Of Sert Genetic Variation

SERTs and have proven useful as an accessible source of SERT genomic DNA in association studies (Lesch et al, 1996), although the function of lymphocyte SERT is unclear (however, see Serafeim and Gordon, 2001 Serafeim et al., 2002). SERTs are also expressed in placenta (Balkovetz et al., 1989 Nguyen et al., 1999), where they may participate in restricting 5-HT access to the fetus, except under defined conditions. SERTs are also found on pulmonary endothelial cells and smooth muscle (Lee and Fanburg, 1986 Lee et al., 1989 Eddahibi et al., 2001), and SERT activity appears critical for hypoxia-in-duced smooth muscle cell proliferation, which suggests that SERT alleles could influence risk to pulmonary hypertension. Thus, although disrupted 5-HT signaling has long been considered relevant for psychiatric disorders, SERT dysfunction might also support more peripherally based phenotypes (Blakely, 2001), with phenotypes linked to GI, placenta and pulmonary dysfunction reasonable...

Use of Cholinesterase Inhibitors in Other Dementia Related Illnesses

With the prevalence of cardiovascular diseases such as hyperlipidemia, diabetes, hypertension, which may over time lead to cerebrovacular disease, there is a direct correlate between the presence of vascular disease and dementia. Studies have shown that there is also a cholinergic deficit in vascular dementia due to ischemia to neurons in the basal forebrain and the cholinergic pathways. Thus it makes sense to treat vascular dementia with cholinesterase inhibitors. In the studies thus far, patients with vascular dementia, who were treated with either donepezil, rivastigmine, or galantamine have shown improvement in cognition, behavior, and activities of daily living 71 . Black and colleagues studied 603 patients with vascular dementia in a randomized, double-blind, placebo-controlled study. Their result shows that donepezil was well tolerated and that patients who were on donepezil had significant improvement in the areas of cognition and activities of daily living 72 .

Class DTarget Maintains Physiological Functions in Normal and Disease States

Examples of such targets include the coagulation factor inhibitors (e.g., FIX, FXa and thrombin), which are critical to maintain a physiological level of homeostasis hence, inhibition of these targets carries inherent bleeding liabilities. Likewise, all current anti-arrhythmic drugs (e.g., amiodarone, lidocaine, dofetilide), while effective in treating life-threatening arrhythmias, all carry significant liability for mechanism-based pro-arrhythmic effects and the potential for sudden death. The biomarker challenges for this class are defining the fine balance needed between efficacy in the disease context and expected safety limitations. Biomarkers that define the acceptable therapeutic index are key to the successful utility of drugs that modulate such targets. However, targets in this class do not necessarily exhibit narrow safety margin for clinically meaningful adverse effects. Significant examples are the L-type Ca2+ channel blockers. The L-type Ca2t channel is an essential...

Hints Of Phenotypes For Variant Sert Alleles From Genetic Studies In Mouse And

In addition to the gut, pulmonary function has been explored recently in SERT knockout mice (Eddahibi et al., 2001). As expected from the notion that a single gene encodes SERT proteins in the brain and periphery, the homozygous SERT knockout eliminates SERT immunoreactivity in pulmonary smooth muscle cells and 5-HT uptake capacity. Interestingly, 5HT and SERT have been implicated in the proliferation of pulmonary smooth muscle cells arising from hypoxia (Lee et al., 1989 Eddahibi et al., 2001). Loss of SERT in the knockouts eliminates the 5-HT-triggered smooth muscle cell proliferation. Conceivably, elevated SERT expression, as provided by a gain-of-function variant, could increase risk for 5-HT dependent pulmonary hypertension (Eddahibi and Adnot, 2002). Overall, the existing studies with SERT promoter polymorphisms point to anxiety and affective disorders, alcoholism, autism, and OCD as important syndromes for which novel SERT polymorphisms might increase risk and thus be study...

Cardiovascular diseases

An excessive generation of superoxide may be a central component of a number of cardiovascular diseases including hypertension, atherosclerosis and hyper-lipidemia.56 One of the mechanisms by which this free radical contributes to hypertension is the inactivation of NO generated from endothelial cells. Endogenous endothelium-derived NO regulates blood pressure by vasodilation. The coupling of superoxide ions with NO decreases its availability thus, overproduction of superoxide diminishes blood vessel tone and promotes hyperten-sion.34 In spontaneously hypertensive rats, treatment with the SOD mimetic M40403 removed superoxide anions and prompted the return to near-normal blood pressure. It was unclear whether this restoration of function was due to prolonged half-life of NO or inhibited formation of peroxynitrite. Superoxide and its product, peroxynitrite, also participate in the development of atherosclerotic lesions (hardening of the arteries) by stimulating lipid peroxidation. In...

Thiols sulphides and other sulphur groups

Thiol and sulphide groups are not usually introduced into leads in SAR studies because they are readily metabolised by oxidation (see Table 12.1). However, thiols are sometimes introduced into a lead structure when improved metal chelation is the objective of the SAR study. For example, the antihypertensive captopril was developed from the weakly active carboxyacylprolines by replacement of their terminal carboxylic acid group with a thiol group, which is a far better group for forming complexes with metals than carboxylic acids (see section 9.12.2).

Implications for New Integrated Treatments

Over the past 20 years, the noninvasive evaluation of diastolic function has mainly relied on echo-Doppler analysis of how blood volume enters the ventricle, which largely depends on its loading conditions. One approach is to evaluate the degree of ventricular untwist that occurs during diastole 14 , either by speckle tracking echocardiography 10 or by velocity vector imaging, a new ultrasound technique that is angle-independent and thus provides an avenue to evaluate the short-axis mechanics of the left ventricle 15 . Sampling of the descendant myo-cardial band segment responsible for systole and of the ascendant band responsible for diastole has recently been performed by Vannan and colleagues 16 . The results revealed that normal and hypertensive patients disclosed a similar peak twist velocity (1.9 + - 0.2 versus 2.3 + - 0.2 cm s), whereas untwist was significantly less in hypertensive patients (1.7 + - 0.1 versus 1.1 + - 0.1 cm s), suggesting that early diastolic dysfunction can...

Fatal familial insomnia FFI

Hypersomnia or insomnia are well known to occur in CJD, and were reported by Heidenhain in one of his original cases. Nevertheless, a new disease was later described, in which the insomnia was very severe.44 These patients also had autonomic symptoms such as hypertension, tachycardia, hyperhydrosis and hyperthermia. Dysarthria, dysphagia, ataxia and myoclonus developed later. Because of the predominance of the sleep abnormalities, this variant of prion disease was termed fatal familial insomnia. The pathological features include severe destruction of the thalamic nuclei with astrogliosis, but without spongiform changes or amyloid deposits.

[24 Measuring Reactive Oxygen Species Inhibition of Endothelin Converting Enzyme

However, high levels of reactive oxygen species (ROS) can be cytotoxic. Superoxide generated by the NADPH oxidase in neutrophils can damage endothelial cells.1'3'6 Ischemia and reoxygenation can lead to the production of high levels of ROS inside endothelial and smooth muscle cells, which can also damage vascular cells. Superoxide may also play a role in the pathophysiology of hypertension angiotensin II activates endothelial cell production of superoxide, which decreases the bioavailability of NO, leading to vasoconstriction.7'8

Crataegus laevigata Poir Dc

Hawthorn fruit is one of the most widely used of all cardiotonics throughout Europe and the United States. It possesses myriad beneficial actions on the cardiovascular system, including documented effects as an antioxidant, an ability to increase coronary output and mildly lower blood pressure and cholesterol, and the ability to promote a slow and steady heartbeat, among other uses. The two most widely used species are C. laevigata and C. monogyna. These are considered to be medicinally interchangeable. Additional species of Crataegus that share a similar chemical profile may also be used interchangeably. However, most research has been done with these two species. Now that there is more of an amalgamation of Asian and Western herb suppliers, Asian species of Crataegus may be mixed up with the Western species. These species are readily distinguished from each other.

Regulation of prostaglandin synthesis in mesangial cells

As in other cell types, induction of COX-2 mRNA and or protein in mesangial cells is strongly suppressed by glucocorticoids 32 , Partial inhibition of COX-2 is also obtained by the immunosuppressive drug cyclosporine A, which is widely used to prevent transplant rejection ( 24 and unpublished results). It may be linked to cyclosporine A-related hypertension, a common adverse effect of this drug.

Crataegus monogyna Jacq

Hawthorn fruit is one of the most widely used of all cardiotonics throughout Europe and the United States. It possesses myriad beneficial actions on the cardiovascular system including documented effects as an antioxidant, an ability to increase coronary output and mildly lower blood pressure and cholesterol, and the ability to promote a slow and steady heartbeat, among other uses. The two most widely used species are C. laevigata and C. monogyna. These are considered to be interchangeable. Additional species of Crataegus that share a similar chemical profile may also be used interchangeably. However, most research has been done with these two species. Now that there is more of an amalgamation of Asian and Western herb suppliers, Asian species of Crataegus may be mixed up with the Western species. These are readily distinguished macroscopically.

Potentiation Of Opioidbased Anesthesia

A sufficient blockade of reflex mechanisms is already obvious during the induction of anesthesia when the maneuver of laryngoscopy and intubation results in an intense nociceptive stimulus. This is followed by defense mechanisms with an activation of the sympathetic nervous system, and a stimulation of the cardiovascular system with tachycardia and hypertension. It therefore is mandatory to block such reflex mechanisms by using an opioid for induction of anesthesia (e.g., fentanyl 0.2-0.5 mg 70 kg body weight, alfentanil 2-3 mg 70 kg body weight or remifentanil 0.5 mg 70 kg body weight) together with the hypnotic (i.e., etomidate, propofol, or a barbiturate). This results in stabilization of the cardiovascular system and a reduction in the dose of the hypnotic, which is necessary to induceunconsciousness for the induction of anesthesia. Such stabilization not only is reflected in blood pressure and heart rate but also in the stress-related plasma level of epinephrine and...

Flavonoids and Cardiovascular Disease

Epidemiologic studies have found an inverse association between flavonoid intake and risk of cardiovascular disease.51 Mechanistically, most flavonoids can increase the resistance of LDL to oxidation in vitro however, ex vivo investigations of LDL oxidation in human studies have not proven consistent. There is a body of evidence showing that flavonoids have effects on other atherogenic mechanisms. For example, flavanols inhibit smooth muscle cell proliferation52 and flavanones reduce blood lipids.53 Flavonoid-rich grape juice, red wine, and coca are antithrombotic as they inhibit platelet aggregation and extend bleeding time.54 Animal and in vitro studies and human intervention trials are largely consistent in showing that flavonoids can improve endothelial function and may reduce blood pressure. In human intervention trials, black tea, cocoa, red wine, and soy flavonoids promote endothelial-dependent vasodila-tion and improve vascular dysfunction via actions on nitric oxide...

Secondary Stroke Prevention

Include the identification and modification of risk factors. In most instances, data on the potential benefits of risk-factor management for secondary stroke prevention have been extrapolated from studies focused on primary prevention. In the last few years, however, a body of evidence has shown that antihypertensive therapy decreases recurrences by one-third among subjects who have already suffered a first stroke.99-101 Cigarette smoking increases the risk of stroke 1.5-fold and should be intensely discouraged.102 Although specific evidence regarding the benefits of secondary stroke prevention is still lacking, it has been suggested that statins may reduce the incidence of first stroke by 30 in patients with symptomatic coronary artery disease or hypercholesterolaemia, and a similar efficacy might be expected to occur in patients with prior stroke.103 Nevertheless, there is still a large gap between the benefits of risk-factor control in reducing recurrences as reported by several...

Primary Angiitis Of The

Histological verification is not only to confirm the vasculitis, but to exclude other diagnoses which may mimic vasculitic syndromes, such as multiple sclerosis or its variants, primary brain lymphoma, infectious encephalitis, amyloid angiopathy, vascu-lopathy due to hypertension and or athersclero-sis.8,15-17 Therefore, histological verification is necessary in patients who are evaluated for the differential diagnosis of vasculitis. In addition, tissue diagnosis is important in these patients before initiating long-term immunosuppressive treatment that is known to have significant complications. Although limited in number, it has been our experience to see patients who presented with relatively acute onset of multifocal neurological signs and symptoms, who had changes consistent with vasculitis on their MRIs and angiographies, and in whom brain biopsy disclosed non-specific ischaemic changes or was not diagnostic. After treating the acute episode, we withheld long-term...

Mechanism Of Action

Colchicine also exhibits a variety of other pharmacological effects. It lowers body temperature, increases the sensitivity to central depressants, depresses the respiratory center, enhances the response to sympathomimetic agents, constricts blood vessels, and induces hypertension by central vasomotor stimulation. It enhances GI activity by neurogenic stimulation but depresses it by a direct effect, and alters neuromuscular function.

Sea Anemone K Channel Toxin Structures

The third group (SAK-III) of toxins belongs to the P-defensin fold family which includes peptides of various origins, including human (produced by neu-trophils and epithelial cells), snake, Platypus and sea anemone. These display antimicrobial, or, analgesic or myonecrotic activities (Torres and Kuchel 2004). SAK-III peptides include the BDS (Blood Depressing Substances) toxins, two very similar 43 amino acid peptides isolated from A. sulcata extracts in 1985 (Beress et al. 1985) and originally characterized for their antihypertensive and antiviral activities. BDS-I was structurally characterized in 1989 (Driscoll et al. 1989a, b) and BDS-I and BDS-II activities on Kv channels were described 13 years later (Diochot et al. 1998). APETx1, a 42 amino acid peptide isolated from Anthopleura elegantissima also belongs to the family of SAK-III peptides (Diochot et al. 2003). Both BDS-I and APETx1 display three disulfide bridges, paired in the C1-C5, C2-C4, C3-C6 connection which stabilizes...

Nervous system vasculitis secondary to drugs and substance abuse

Earlier, such changes are not always due to vasculi-tis. The underlying mechanism responsible for the vascular events related to drug use or substance abuse may be platelet and coagulation factor abnormalities, accelerated atherosclerosis, foreign body embolism, cerebral vasospasm, hypertension, and rarely endocarditis and meningitis.59

Alpha2Adrenergic Agonists

A2-Adrenergic agonists (e.g., clonidine) are available for epidural administration for neuropathic pain (Eisenach et al. 1995). Hypotension and bradycardia may result from use of these agents, but the risk is reduced if low doses are used. Adverse effects include hemodynamic instability. There is a risk of rebound hypertension with acute withdrawal of therapy. Topical clonidine gel is being developed for use in neuropathic pain states. Tizanidine, another a2-adrenergic agonist, is used for muscle relaxation.

AAdrenergic Receptor Agonists

Clonidine 3.35 bears a formal resemblance to b-phenylethylamine. This compound and related imidazolines have attracted interest as antihypertensive agents to reduce blood pressure. They act as adrenergic agonists at a2-receptors. Whereas the a1-receptors are post-synaptic receptors, stimulation of which induces the adrenergic pharmacological effects, the a2-receptors are pre-synaptic receptors and binding to them leads to a regulation and an inhibition of the release of the

Insights from Health and Disease

Summary The identification and characterization of the processes of G proteincoupled receptor (GPCR) activation and inactivation have refined not only the study of the GPCRs but also the genomics of many accessory proteins necessary for these processes. This has accelerated progress in understanding the fundamental mechanisms involved in GPCR structure and function, including receptor transport to the membrane, ligand binding, activation and inactivation by GRK-mediated (and other) phosphorylation. The catalog of Gsa and GP subunit polymorphisms that result in complex phenotypes has complemented the effort to catalog the GPCRs and their variants. The study of the genomics of GPCR accessory proteins has also provided insight into pathways of disease, such as the contributions of regulator of G protein signaling (RGS) protein to hypertension and activator of G protein signaling (AGS) proteins to the response to hypoxia. In the case of the G protein-coupled receptor kinases (GRKs),...

Vitamin B6 Deficiency

Antituberculous drug isoniazid and the antihypertensive drug hydralazine.23 Symptoms consist of symmetrical tingling and pain, and are reversible after stopping medication. The neuropathy could be prevented by daily supplementation of 10-20 mg of B6 per day during treatment with these drugs. Paradoxically, the prolonged administration of extremely high doses of pyridoxine may actually cause a disabling sensory neuropathy.24

Angiotensin Receptors

The AT1 and AT2 receptors have little sequence homology. Most of the known biological effects of AngII are mediated by the AT1 receptor. Consistent with its functional preeminence, the AT1-receptor gene contains a polymorphism (A1166C) that is associated with hypertension, hyper-trophic cardiomyopathy, coronary artery vasoconstriction, and aortic stiffness, while preeclampsia is associated with the development of activating autoantibodies against the ATt receptor. Potential roles for the AT2 receptor include antiproliferative, proapoptotic, vasodilatory, and antihypertensive effects.

Potential Beneficial Effects of Marine Algal Sterols on Human Health

Antihypertensive and antihypercholesterolemic activities 195 has been well recognized due to their valuable health beneficial effects. Therefore, isolation and characterization of novel functional ingredients with biological activities from marine algae have gained much attention. Sterols are important structural component of cell membranes. It has been reported that plant sterols exhibit various beneficial biological activities such as hypercholester-olemic, antioxidant, anticancer, antidiabetic, antihypertensive, anti-inflammatory, antifungal, and antibacterial activities. Marine algae

Typeii Diabetes Mellitus

Reaven (1988) suggested that insulin resistance might be a common denominator for obesity, Type-II diabetes hypertension and hyperlipidaemia (metabolic syndrome) and should be treated rigorously to avoid coronary heart disease, the most common cause of morbidity and mortality in Type-II diabetes mellitus. However, it still remains to be proven that effective blood glucose control will reduce the mortality of the disease (Turner and Holman, 1990).

Benzothiadiazines and Related Compounds

Benzothiadiazines ( thiazides ) and related diuretics are the most frequently used class of antihypertensive agents in the U.S. Thiazides block the Na+-Cl- symporter and have the same pharmacological effects and are generally interchangeable with appropriate dose adjustment (see Chapter 28). Since their pharmacokinetics and pharmacodynamics differ, these drugs do not necessarily have the same clinical efficacy in treating hypertension. REGIMEN FOR ADMINISTRATION OF THE THIAZIDE-CLASS DIURETICS IN HYPERTENSION When a thiazide diuretic is used as the sole antihypertensive drug (monotherapy), its dose-response curve for lowering blood pressure in patients with hypertension should be

P450catalyzed arachidonic acid metabolism in man

Investigation of P450-catalyzed arachidonic acid metabolism of the human kidney cortex in postmortem subjects showed synthesis of both expoxygenases (14,15-, 11,12- and 8,9-EETs) and m-hydroxylase products (19- and 20-HETEs) 131,151 . Although qualitatively similar, there was more than 100-fold quantitative interindividual variability. Preliminary studies have suggested that P-450-derived arachidonic acid metabolites may also be related to hypertension in man however, up to now no conclusive evidence has been provided.

Pharmacological Effects

Essentially all of the therapeutic and adverse effects of guanadrel result from functional sympathetic blockade. The antihypertensive effect is achieved by a reduction in peripheral vascular resistance that results from inhibition of a receptor mediated vasoconstriction. Consequently, arterial pressure is reduced modestly in the supine position when sympathetic activity is usually low, but the pressure can fall considerably when reflex sympathetic activation is needed to maintain arterial pressure, such as assumption of the upright posture, exercise, and depletion of plasma volume. Plasma volume often expands, which may diminish the antihypertensive efficacy of guanadrel and require administration of diuretic to restore the antihypertensive effect.

Angiotensinconverting Enzyme Inhibitors

The ability to reduce levels of angiotensin II (AnglI) with orally effective inhibitors of angiotensin-converting enzyme (ACE) represents an important advance in the treatment of hypertension. Captopril (Capoten), enalapril (Vasotec), lisinopril (prinivil), quinapril (accupril), ramipril (altace), benazepril (Lotensin), moexipril (univasc), fosinopril (monopril), trandolapril (mavik), and perindopril (aceon) have proven to be very useful for the treatment of hypertension because of their efficacy and their very favorable profile of adverse effects, which enhances patient adherence. Chapter 30 presents the pharmacology of ACE inhibitors in detail. The ACE inhibitors appear to confer a special advantage in the treatment of patients with diabetes mellitus, slowing the development and progression of diabetic glomerulopathy. They also are effective in slowing the progression of other forms of chronic renal disease, such as glomeru-losclerosis, and many of these patients also have...

Glucocorticoid Receptor

1,2-Dihydroquinolines I are promising glucocorticoid receptor (GCR) antagonists, and therefore potential drugs for the treatment of various pathological states. The GCR is a member of the cytoplasmic steroid receptors, which are the target molecules for the actions of endocrine gluco- and mineralo-corticoid, oestrogenic and protestagenic hormones. The lipid soluble glucocorticosteroids diffuse across the cell membrane in order to bind to the GCR. This interaction initiates a variety of signal transcription reactions and translocation of the steroid-receptor complex to the cell nucleus. On binding to nuclear glucocorticoid response elements, the steroid either causes transactivation, the active expression of biologically active proteins, or transrepression, the inhibition of protein expression. The protein profile thus generated modulates essential physiological processes such as energy and bone metabolism, cell growth and differentiation, maintenance of blood pressure and immune...

Stand Alone versus Synergic Biomarkers

Generally, a stand-alone biomarker must have a very high level of discrimination to accurately detect a disease with a c-statistic greater than 90 such as troponins. Since this level of discrimination is unusual for prognosis, these risk markers are generally synergistic in that several markers are combined to achieve a high discrimination for total risk. Thus, risk for coronary disease is assessed using the established risk factors of age, hypertension, smoking history, lipid status, and body mass index (BMI) 26 . For example, a recent test for polymorphism and progression to type 2 diabetes showed an overall RR of 1.54 53 . Clearly, as a stand-alone marker, it would show little or no clinical usefulness since Fig. 1 indicates that an OR of 1.5 is about equivalent to a c-statistic of about 0.55. This means that at a 15 FPR the TPR would be about 20 . Assuming a prevalence of disease of 1 , this would translate into a PPV of 1.3 ( true positives true positives + false positives x 100)...

Bronchial Smooth Muscle

Smooth muscle cell protein synthesis and hypertrophy (27) and mitogenesis (28) have been observed to be stimulated by TXA2 Whether or not has direct mitogenic properties is debated (See 29 for review), but evidence of mitogenic effects of TXA2 on smooth muscle has been presented (28,30-33). The observations of Hanasaki, et al (34) and of Grosser, et al (35) suggest that TXA2 acts as a mitogen only in the presence of insulin or growth factors such as platelet-derived growth factor. Futher evidence of the potentiating effects of TXA2 on mitogenesis induced by 5-HT (33) and by thrombin (36) supports this concept The role of TXA2-stimulated mitogenesis in arterial smooth muscle proliferation in human disease is uncertain, but it has been speculated that TXA2 contributes to the pathophysiology of hypertension (20) and to coronary artery smooth muscle proliferation following revascularization (29,36).

Class A Disease Specific Target

Examples of such targets include the coagulation factor inhibitors (e.g., FIX, FXa, and thrombin), which are critical to maintain a physiological level of homeostasis hence, inhibition of these targets carries inherent bleeding liabilities. Similarly, all current antiarrhythmic drugs (e.g., amiodarone, lido-caine, dofetilide), while effective in treating life-threatening arrhythmias, all carry significant liability for mechanism-based pro-arrhythmic effects and the potential for sudden death. The biomarker challenges for this class are defining the fine balance needed between efficacy in the disease context and expected safety limitations. Biomarkers that define the acceptable therapeutic index are key to the successful utility of drugs that modulate such targets. However, targets in this class do not necessarily exhibit a narrow safety margin for clinically meaningful adverse effects. Significant examples are the L-type Ca2+ channel blockers. The L-type Ca2+ channel is an essential...

Vasopeptidase Inhibitors And

Vasopeptidase inhibitors are a novel group of drugs that simultaneously inhibit ACE and neutral endopeptidases (NEPs) and are effective antihypertensive agents. NEPs are responsible for the enzymatic degradation of atrial and brain natriuretic peptides. Inhibitors of NEPs therefore are expected to increase circulating levels of these natriuretic hormones and on this basis have been investigated as therapeutic agents in heart failure. Studies suggest that the vasopeptidase inhibitor omapatrilat is comparable to ACE inhibitors with respect to improving exercise capacity, decreasing symptoms, and reducing the risk of death and hospitalization in chronic heart failure, but is more frequently associated with symptomatic hypotension. Omapatrilat is not approved by the FDA.

Thiazides and related diuretics

In the management of hypertension a low dose of a thiazide, e.g. bendroflumethiazide 2.5 mg daily, produces a maximal or near-maximal blood pressure lowering effect, with very little biochemical disturbance. Higher doses cause more marked changes in plasma potassium, sodium, uric acid, glucose, and lipids, with little advantage in blood pressure control. For reference to the use of thiazides in chronic heart failure see section 2.5.5. Bendroflumethiazide is widely used for mild or moderate heart failure and for hypertension alone in the treatment of mild hypertension or with other drugs in more severe hypertension. Xipamide and indapamide are chemically related to chlortalidone. Indapamide is claimed to lower blood pressure with less metabolic disturbance, particularly less aggravation of diabetes mellitus. Pregnancy Thiazides and related diuretics should not be used to treat gestational hypertension. They may cause neonatal thrombocytopenia, bone marrow suppression, jaundice,...

Diastolic Heart Failure

Patients with diastolic heart failure are typically dependent upon preload to maintain adequate cardiac output. While patients with symptomatic volume overload will benefit from careful modulation of intravascular volume, volume reduction should be accomplished gradually and treatment goals reassessed frequently. In addition to cautious volume management, it is important to maintain synchronous atrial contraction in such patients, which maintains adequate left ventricular filling during the latter phase of diastole. Cardiac function is often severely impaired if patients with diastolic heart failure develop atrial fibrillation, particularly in the context of suboptimal ventricular rate control. Meticulous control of the ventricular rate with drugs that slow AV conduction is mandatory (see Chapter 34) and restoration of sinus rhythm should be considered. It is also important to evaluate and treat conditions that are associated with dynamic abnormalities of diastolic function, such as...

Subunits Associated with Complex Phenotypes

While no variants of the P- and y-subunits have been associated with monogenic disorders, polymorphisms have been associated with a variety of complex phenotypes. For example, a single-base substitution (c.825C T) of the GP3 gene (GNB3) has been associated with hypertension. The variant leads to alternative splicing that is predicted to generate shortened GP3 proteins (56), which may cause enhanced G protein signaling (56-58). Biochemically, this may result from an abnormal stability of the functional interactions of the shortened GP3 proteins (57).

Antioxidant Vitamins and CoQ10 in Diabetes in Relation to Vascular Disease

There are no published studies on the role of CoQ10 in patients with diabetes associated with vascular disease. However, in several studies CoQ10 has been shown to be beneficial in patients with angina, CHD, heart failure, hypertension and cardiomyopathy (Kuklinski et al., 1994 Karlsson et al., 1996, 1997 Barbiroli et al., 1997 Lagendijk et al., 1997). In

Cardiovascular Effects Of Calcium Ion Channel Blockers

All Ca2+ antagonists yet developed are vasodilators. Vasodilation is a result of the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca2+. Coronary artery muscle tone is reduced in healthy humans but is particularly pronounced in a condition of coronary spasm. Peripheral arteriole resistance is reduced more than venous beds. The vasodilatory effect of these drugs is the basis for their use in the control of angina and hypertension.13 Although verapamil, nifedipine, and diltiazem can cause vasodilation, they are not equally effective at blocking the Ca2+ channels found in various tissues. The phenyl-alkylamine verapamil and the benzothiazepine diltiazem have both cardiac and vascular actions. These drugs have antiarrhythmic, antianginal, and antihypertensive activity. They depress the cardiac neural network, and so slow sinus node automaticity, prolong atrioventricular (AV) nodal conductance, and depress myocardial contractility, as well as reduce...

Total or individual assays

It has been suggested that evaluating M and NM excretions separately could increase the diagnostic sensitivity of these tests, because in some cases pheochromocytoma can secrete predominantly E, whereas in others the predominant catecholamine is NE, DA or Dopa.15 In a retrospective study of 372 patients with sustained hypertension, for whom the determination of 24-h urinary metanephrines or VMA was ordered, Kairisto et al. found that evaluating NM excretion has better diagnostic specificity at 100 diagnostic sensitivity than did the sum of NM and M excretions. They also found that the determination of VMA in addition to NM and MN did not yield additional diagnostic information for any of the patients.16 Similar findings were reported by Gerlo and Sevens after reviewing the measurement of catecholamines and their metabolites in 19 patients with pheochromocy-toma.17 They commented that assays of total catecholamines and total metanephrines are diagnostically inadequate, and that NE E...

Endothelin Receptor Antagonists

Endothelin-1 is a 21-amino acid peptide that is produced in the vascular endothelium, which plays a role in the regulation of smooth muscle contraction. Two types of endothelin receptors, ETa and ETB, have been identified on smooth muscle. The physiological role these play varies depending on the location of the receptor. Overall, the receptors are linked to a Gq-protein and when activated, results in the formation of IP3. This, in turn, results in the release of calcium by the sacroplas-mic reticulum that results in increased smooth muscle contraction and vasoconstriction. It is of interest to note that ETB receptors located on the endothelium have a slightly different role than those found on the vascular smooth muscle. When the endothelium ETB receptors are stimulated, NO is formed from l-arginine. The NO that is released produces vasodila-tion in much the same fashion as nitroglycerin. This effect is generally transient, whereas the overall effects of stimulation of the vascular...

Phosphodiesterase Type 5 Inhibitors

As discussed throughout this chapter, the cyclic nucleotide phosphodiesterases constitute a group of enzymes that catalyze the hydrolysis of various cyclic nucleotides including cAMP and cGMP. The contractility of all muscle types is regulated primarily by reversible phosphorylation of the protein myosin. The phosphorylation of myosin allows it to interact with actin, which results in muscle contraction. Through different mechanisms, cAMP and cGMP interfere with the ability of myosin to be phosporylated and or interact with actin. This, in turn, results in muscle relaxation. Agents that interfere with the degradation of the cyclic nucleotide have usefulness in treating hypertension, erectile dysfunction, etc. Phosphodiesterase type 5 (PDE5) is responsible for the catalytic hydrolysis of cGMP in the smooth muscle of the arteries in the penis and lungs. Inhibitors of this particular phos-phodiesterase have been shown to relax arteries in the penis, thus allowing the corpus cavernosum to...

HSPsAntiHSPs as Biomarkers of Atherothrombosis

Different studies have analyzed the levels of circulating HSPs. Among them, levels of HSP60 are increased in patients with carotid atherosclerosis, suggesting its potential role as a diagnostic biomarker 23 . In patients with borderline hypertension, serum HSP60 levels were associated with intima-media thickness, a surrogate marker of atherosclerosis 24 . An inverse relation between HSP70 and atherosclerosis has been reported by several groups. Whereas HSP70 is detectable in serum of nondiseased individuals 95 , low serum HSP70 levels have been suggested to predict the development of atherosclerosis 52-54 . In hypertensive patients, increased concentrations of circulating HSP70 correlated with decreased intima media thickness 52 . In another study by Zhu et al., high serum levels of HSP70 were found to be associated with a low risk of coronary artery disease 53 . We have reported that plasma HSP70 concentrations were decreased in patients with carotid atherosclerosis relative to...

Other Acid Suppressants And Cytoprotectants

Rebamipide acid) is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet (gastrom 12-sulfodehydroabietic acid monosodium), which appears to increase the formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan. Carbenoxolone, a derivative of gly-cyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. Unfortunately, carbenoxolone inhibits the type 2 isozyme of 11 -hydroxysteroid dehydrogenase, which protects the mineralocorticoid receptor from activation by cortisol in the distal nephron it therefore causes hypokalemia and hypertension due to excessive mineralocorticoid receptor activation (see Chapter 59). Bismuth compounds (see Chapter 37) may be as effective as cimetidine in...

Management of arrhythmias

In symptomatic paroxysmal atrial fibrillation, ventricular rhythm is controlled with a beta-blocker. Alternatively, if symptoms persist or a beta-blocker is not appropriate, an oral anti-arrhythmic drug such as sota-lol, flecainide, propafenone, or amiodarone can be given (see also Paroxysmal Supraventricular Tachycardia below, and Supraventricular Arrhythmias). In selected patients with infrequent episodes of symptomatic paroxysmal atrial fibrillation, sinus rhythm can be restored using the 'pill-in-the-pocket' approach this involves the patient taking oral flecainide or propafenone to self-treat an episode of atrial fibrillation when it occurs. All patients with atrial fibrillation should be assessed for their risk of stroke and the need for thromboprophylaxis. Anticoagulants (section 2.8) are indicated for those with a history of ischaemic stroke, transient ischaemic attacks, or thromboembolic events, and those with valve disease, heart failure, or impaired left ventricular...

Therapeutic Implications

Among the other traditional treatments for hyperlipidemia, hypertension, and diabetes mellitus are other pharmacologic agents that have been shown to decrease chemokine levels. Fibrates may indirectly downregulate MCP-1 by inducing PPARs (148) and via reduction of CRP (143), although it has also been shown in one study that fenofibrate increased MCP-1 and IL-8 secretion (148). Medications that inhibit the renin-angiotensin axis have a role in blocking chemokine production. For example, the angiotensin-converting enzyme (ACE) inhibitor enalapril was able to decrease serum MCP-1 levels in patients with acute myocardial infarction (150). Other more recent studies have shown that angiotensin receptor blockers (ARBs) also decreased plasma MCP-1 concentrations, and combination therapy with either an ACE inhibitor or ARB plus a statin led to further decreases when compared with ACE inhibitor ARB monotherapy (reviewed in Ref. 143). Finally, the antidiabetic glitazones have been proven to...

Extraarticular Disease Manifestations

Cardiovascular (CV) morbidity and mortality in RA occur at rates greater than would be expected from the profile of established CV risk factors. Diabetes mellitus, hypercholesterolemia, hypertension, cigarette smoking, and obesity are generally powerful classifiers of CV risk and when comparing the profiles of these risk factors in people with and without RA, they are similar. Thus, there must be RA-specific factors explaining the increased risk. Dividing the patients in younger and older patients demonstrates that such factors are more common in the younger age group. In older patients, the

Risks For Obesity Diabetes And Cardiovascular Disease 41 Obesity

Obesity is a major public health problem in the United States, with an increasing prevalence in both adults (37,38) and children (39). Obesity increases the risk of morbidity and mortality from associated diseases such as diabetes, hypertension, coronary heart disease, and cancer (40-42). Diets have been the traditional approach to dealing with excessive weight. Robert Atkins (43) popularized the use of the ketogenic diet to deal with weight gain. This type of ketogenic diet is a low-carbohydrate but high-protein formulation and consequently is fundamentally different from diets used for seizure control.

Angiotensin Antagonists

Any remaining questions that may have challenged the pathophysiological importance of the renin-angiotensin system (RAS) have been dispelled by the established and growing success of the angiotensin converting enzyme inhibitors (ACEIs) in the clinic. For example, captopril, first introduced in 1981, and then enalapril have become established as front-line treatments for hypertension (1,2), and exciting results have emerged from large clinical trials regarding the usefulness of ACEIs in congestive heart failure (CHF) and diabetic nephropathy (3-6). The realization that ACEIs would have tremendous commercial success caused an enthusiastic response from the pharmaceutical industry to identify other opportunities to interfere therapeutically with the RAS. It was from this intense period of research, during the 1980s, that the first nonpeptide angiotensin receptor antagonists were developed. The prototype compound and most clinically advanced of these, losartan (otherwise known as Ex 89,...

Physiology of the Ras Potential Therapeutic Targets

The octapeptide angiotensin II (AII) is the main effector hormone of the RAS and an important regulator of cardiovascular homeostasis. Simplistically, AII causes vasoconstriction and salt and water reabsorption and, by virtue of these, influences electrolyte balance, blood volume, and arterial blood pressure (13). These responses are mediated directly by an effect of AII on the systemic vasculature, in the kidney, and through release of aldosterone. The effects on cardiovascular homeostasis are mediated both peripherally (14,15) and centrally (16). It is now understood that overactivity of the RAS is a key factor in the pathogenesis of essential hypertension (13,17) and CHF (18). A schematic of the RAS showing the three established sites for pharmacological therapeutic intervention is shown in Figure 1.

Betaadrenoceptor blocking drugs

Many beta-blockers are now available and in general they are all equally effective. There are, however, differences between them, which may affect choice in treating particular diseases or individual patients. Intrinsic sympathomimetic activity (ISA, partial agonist activity) represents the capacity of beta-blockers to stimulate as well as to block adrenergic receptors. Oxprenolol, pindolol, acebutolol, and celiprolol have intrinsic sympathomimetic activity they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities. Some beta-blockers are lipid soluble and some are water soluble. Atenolol, celiprolol, nadolol, and sotalol are the most water-soluble they are less likely to enter the brain, and may therefore cause less sleep disturbance and nightmares. Water-soluble beta-blockers are excreted by the kidneys and dosage reduction is often necessary in renal impairment. Beta-blockers with a relatively short duration of action have...

Propranolol Hydrochloride

Indications see under Dose Cautions see notes above also avoid abrupt withdrawal especially in ischaemic heart disease first-degree AV block portal hypertension (risk of deterioration in liver function) diabetes history of obstructive airways disease (introduce cautiously and monitor lung function see notes above) myasthenia gravis symptoms of hypoglycaemia and thyrotoxic-osis may be masked (also see notes above) psoriasis history of hypersensitivity may increase sensitivity to allergens and result in more serious hypersensi-tivity response, also may reduce response to adrenaline (epinephrine) (see also section 3.4.3) interactions Appendix 1 (beta-blockers), important verapamil interaction, see also p. 133 Contra-indications asthma (but see notes above), uncontrolled heart failure, Prinzmetal's angina, marked bradycardia, hypotension, sick sinus syndrome, second- or third- degree AV block, cardiogenic shock, metabolic acidosis, severe peripheral arterial disease phaeochromocytoma...

Industrial Development of AT1 Receptor Antagonists for Clinical

Until the late 1980s, the only available angiotensin receptor antagonists were peptides, but this did not deter important experimental studies in patients, where it was demonstrated that intravenously administered saralasin reduced blood pressure in renovascular hypertensives (70). For the first time, this causatively linked endogenous AII in the etiology of hypertension, beyond the previous association with raised plasma renin activity. The susceptibility of saralasin to degradation when given by the oral route and the short half-life if given intravenously meant that it could not be entertained as a serious drug entity. Furthermore, the unsuitability of saralasin was confirmed when it was shown to act as a partial agonist in human volunteers (71). seen moreover, it was considered surprising that an octapeptide receptor interaction could be selectively antagonized by such low-molecular-weight compounds with no gross structural similarity to the endogenous agonist. At a high dose and...

Inactivation of GPCRs

Continuous exposure of a GPCR to an agonist produces a self-limited signal (44) that may be disrupted in disease states. Two examples worthy of discussion are Oguchi disease, caused by disruption of GRK1 inactivation, and essential hypertension associated with GRK4 variants. Disruption of GRK activity is discussed with respect to Oguchi disease and to essential hypertension in separate discussions in Subheading 6.4.3

Challenge for the Future

AT1 receptor antagonists are becoming an increasingly popular choice for the treatment of hypertension, and some believe that this class of compound has the potential to become a first-line treatment option for this indication (114). If the AT1 receptor antagonist hypertension market grows, it will probably be to the detriment of the ACE inhibitors, especially if the lack of side effects (e.g., cough) becomes established as a tangible and generally accepted advantage. Furthermore, it is believed that AII can be generated by enzymes other than ACE (118,119), so that in theory, AT1 receptor antagonists should offer a more specific and complete inhibition of the RAS than the ACEIs can. On the other hand, prolonged clinical treatment with a selective AT1 receptor antagonist could lead to raised plasma AII levels and an action on AT2 receptors. However, the clinical relevance of this latter scenario is currently unknown and, as detailed above, it is even difficult to predict in the...

Esmolol Hydrochloride

Indications short-term treatment of supraventricular arrhythmias (including atrial fibrillation, atrial flutter, sinus tachycardia) tachycardia and hypertension in peri-operative period Cautions see under Propranolol Hydrochloride Contra-indications see under Propranolol Hydro-chloride

Uses of the PCR in research and clinical diagnosis

Genetic mutations that predispose individuals to myocardial infarction a mutation in the angiotensin-converting enzyme (ACE) gene or hypertension (a mutation in the angiotensinogen gene) have recently been identified. Clinicians now are pushing for large population screening programmes to detect these mutations so that affected individuals can be counselled and advised to change their lifestyles or eating habits accordingly.

Physiology and disease relevance

Compounds interacting with several of the adrenoceptors have proven to be important drugs, the primary examples being nonselective -adrenoceptor antagonists for hypertension and heart failure, -adrenoceptor agonists for asthma and a1 -adrenoceptor antagonists for benign prostatic hyperplasia and hypertension (Ruffolo etal. 1995).

AAdrenoceptor Agonists and Antagonists

Drugs interacting with the a-adrenoceptors come from a variety of different chemical classes, including the quinazoline a1-adrenoceptor antagonists for hypertension and benign prostatic hyperplasia (BPH), the imidazoline a2-adrenoceptor agonists for hypertension, glaucoma, and several applications within the central nervous system, and the phenethylamine and imidazoline a1-adrenoceptor agonists, which are commonly used as nasal decongestants. There is currently great interest in the design of a1-adrenoceptor

Assay Development For Ion Channels 431 Biology of Ion Channels

Ion channels are attractive drug targets. Currently more than 30 ion channel targeting drugs are marketed worldwide for use as local anesthetics during minor surgery (blockers of voltage-gated Na+ channels) and to treat a variety of conditions, including epilepsy, chronic pain, cardiac arrhythmia, hypertension, angina, and type II diabetes. Although there are exceptions (Gee et al. 1996), most drugs modulate ion channel function by interfering with either the gating and or permeation processes after binding to receptor sites on the pore-forming a subunits (Hockerman et al. 1997).

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