Vasoactive substances

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Substances released from many cells and tissues in the body, including the endothelium lining blood vessels, endocrine glands, and myocytes in the heart, may affect vascular smooth muscle tone. These substances may stimulate this muscle to cause vasoconstriction or inhibit it to cause vasodilation. As expected, vasoconstriction will increase TPR (and therefore MAP) and vasodilation will decrease TPR (and therefore MAP).

Vasoconstrictors. Many substances produced in the human body cause vasoconstriction under physiological and pathophysiological conditions. Vasoconstrictors of particular importance include:

Catecholamines Angiotensin II Vasopressin Endothelin Thromboxane A2

The major circulating hormones that influence vascular smooth muscle tone are the catecholamines: epinephrine and norepinephrine. These hormones are released from the adrenal medulla in response to sympathetic nervous stimulation. In humans, 80% of catecholamine secretion is epinephrine and 20% is norepinephrine. Stimulation of a^adrenergic receptors causes vasoconstriction. The selective aradrenergic receptor antagonist, prazosin, is effective in management of hypertension because it causes arterial and venous smooth muscle to relax.

Angiotensin II (AglI) is a circulating peptide with powerful vasoconstrictor properties. The formation of Ag II is initiated by the enzyme renin, which converts the plasma-borne precursor angiotensinogen into angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I into the active molecule, Ag II. The location of ACE is ideal for this function because it is found on the surface of endothelial cells in the lungs, which are exposed to the entire cardiac output. The release of renin from specialized cells in the kidneys occurs in response to sympathetic stimulation and when there is a decrease in renal blood flow.

Angiotensin II causes vasoconstriction by direct stimulation of ATX receptors on the vascular smooth muscle. It also enhances release of the neu-rotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active.

Vasopressin (antidiuretic hormone) is a peptide synthesized in the hypothalamus and secreted from the neurohypophysis of the pituitary gland. This substance plays an important role in the long-term regulation of blood pressure through its action on the kidney to increase reabsorption of water. The major stimulus for release of vasopressin is an increase in plasma osmolarity. The resulting reabsorption of water dilutes the plasma toward its normal value of 290 mOsM. This activity is discussed in more detail in Chapter 10 (the endocrine system) and Chapter 19 (the renal system).

Vasopressin also plays an important role in short-term regulation of blood pressure through its action on vascular smooth muscle. This hormone is the most potent known endogenous vasoconstrictor. Two types of vaso-pressin receptors have been identified: V1 receptors mediate vasoconstriction and V2 receptors mediate the antidiuretic effects of this hormone. Specific V1 receptor antagonists of the vasoconstrictor activity of vasopressin are under development.

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only.

Another vasoactive substance produced by the endothelium is thrombox-ane A2 (TxA2). Normally, small amounts of TxA2 are released continuously; however, increased synthesis appears to be associated with some cardiac diseases. Synthesized from arachidonic acid, a plasma membrane phospholipid, TxA2 is a potent vasoconstrictor. Furthermore, this substance stimulates platelet aggregation, suggesting that it plays a role in thrombotic events such as myocardial infarction (heart attack). Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen block formation of TxA2 and reduce formation of blood clots.

Pharmacy application: antihypertensive drugs

Hypertension is the most common cardiovascular disease; in fact, nearly 25% of adults in the U.S. are considered hypertensive. Hypertension is defined as a consistent elevation in blood pressure such that systolic/diastolic pressures are >140/90 mmHg. Over time, chronic hypertension can cause pathological changes in the vasculature and in the heart. As a result, hypertensive patients are at increased risk for atherosclerosis, aneurysm, stroke, myocardial infarction, heart failure, and kidney failure. There are several categories of antihypertensive agents:

• Diuretics. The primary mechanism by which diuretics reduce blood pressure is to decrease plasma volume. Acting at the kidney, diuretics increase sodium loss and, due to the osmotic effects of sodium, increase water loss. The decrease in plasma volume results in a decrease in VR, CO, and MAP.

• Sympatholytics. Sympathetic stimulation of the cardiovascular system may be altered by several mechanisms. Centrally acting agents exert their effects at the vasomotor center in the brainstem and inhibit sympathetic discharge. Reduced sympathetic stimulation of the heart and, especially, the vascular smooth muscle results in some decrease in CO and a marked decrease in TPR. Beta-adrenergic receptor antagonists reduce myocardial contractility and CO. These agents also inhibit the release of renin from the kidney. The resulting decrease in production of angiotensin II leads to vasodilation and a decrease in TPR. Alpha-adrenergic receptor antagonists reduce vascular resistance, therefore reducing blood pressure.

• Vasodilators. Hydralazine causes direct relaxation of arteriolar smooth muscle. An important consequence of this vasodilation, however, is reflex tachycardia (T CO). It may also cause sodium retention (T plasma volume). The resulting increase in CO tends to offset effects of the vasodilator. Therefore, these drugs are most effective when administered along with sympathetic agents such as b-adrenergic receptor antagonists, which prevent unwanted compensatory responses by the heart.

• Ca++-channel blockers. Verapamil has powerful effects on the heart, decreasing heart rate and myocardial contractility (0 CO) and causing some vasodilation. On the other hand, nifedipine is a more potent vasodilator (0 TPR) with weaker myocardial effects. The effects of diltiazem are somewhat intermediate, in that this drug has moderate inhibitory effects on the myocardium and vascular smooth muscle.

• Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors not only cause vasodilation (0 TPR), but also inhibit the aldosterone response to net sodium loss. Normally, al-dosterone, which enhances reabsorption of sodium in the kidney, would oppose diuretic-induced sodium loss. Therefore, coadministration of ACE inhibitors would enhance the efficacy of diuretic drugs.

• Angiotensin II receptor antagonists. These agents promote vasodilation (0 TPR), increase sodium and water excretion, and, therefore, decrease plasma volume (0 CO).

Drug classification Generic agents CO TPR PV

Diuretics

0

0

Thiazides

Hydrochlorothiazide

Loop diuretics

Furosemide

K+-sparing diuretics

Amiloride

Sympatholytics

0

0

Central acting

Methyldopa

ß-Antagonist

Propranolol

0

0

a-Antagonist

Prazosin

0

Vasodilators

0

0

Arterial

Hydralazine

Arterial and venous

Nitroprusside

Ca++-channel blockers

Verapamil

0

0

Nifedipine

0

Diltiazem

0

0

ACE inhibitors

Captopril

0

AgII-antagonists

Losartin

0

Vasodilators. Many substances produced in the human body cause vasodilation under physiological and pathophysiological conditions. Vasodilators of particular importance include:

• Prostacyclin

• Atrial natriuretic peptide

Another metabolite of arachidonic acid is prostacyclin (PGI2). As with TxA2, PGI2 is produced continuously. Synthesized by vascular smooth muscle and endothelial cells, with the endothelium as the predominant source, PGI2 mediates effects that are opposite to those of TxA2. Prostacyclin causes vasodilation and inhibits platelet aggregation and, as a result, makes an important contribution to the antithrombogenic nature of the vascular wall.

First described in the 1980s as "endothelium-derived relaxing factor," nitric oxide (NO) is a vasodilator believed to play a role in regulation of blood pressure under physiologic and pathophysiological conditions. For example, inhibition of NO synthesis under normal conditions and during septic shock results in a significant elevation of blood pressure.

Pharmacy application: nitroglycerin and angina

Angina pectoris (chest pain) is the most common symptom of chronic ischemic heart disease. Angina is caused by an imbalance between the oxygen supply and oxygen demand of the cardiac muscle. Myocardial oxygen demand increases during exertion, exercise, and emotional stress. If coronary blood flow does not increase proportionately to meet this demand, then the affected tissue becomes ischemic and pain develops. This ischemia and pain may be treated pharmacologically with nitroglycerin, a drug that causes vasodilation and an increase in blood flow. However, this effect occurs not only in the coronary arteries, but also in blood vessels throughout the body. Therefore, in addition to improving coronary blood flow, administration of nitroglycerin may decrease systemic blood pressure. The mechanism of action of nitroglycerin involves release of NO in the vascular smooth muscle. Most frequently, this drug is administered in the sublingual form and its effects are apparent within 1 to 3 minutes.

Atrial natriuretic peptide (ANP) is produced by specialized myocytes in the atria of the heart. Secretion is stimulated by increased filling and stretch of the atria in response to plasma volume expansion. The effects of ANP include vasodilation, diuresis (increased urine production), and increased sodium excretion. Taken together, these effects decrease blood volume and blood pressure toward normal.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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