Knockout and overexpression experiments have been reported only for the a1b-adrenoceptor subtype. Knockout of the a1b-adrenoceptor results in impaired vascular responsiveness to phenylephrine, demonstrated both in isolated blood vessels and through measurement of blood pressure responses in anesthetized mice (Cavalli et al. 1997). Cardiac specific overexpression of the a1b-adrenoceptor results in an impairment of cardiac function without cardiomyocyte hypertrophy (Grupp et al. 1998). Increased a1B-adrenoceptor density in the heart impairs the responsiveness to (-adrenoceptor agonists, perhaps as a result of heterologous desensitization (Lemire et al. 1998). In many cases, the particular subtype involved in an a1 -adrenoceptor mediated response has not yet been identified. This is due in part to the lack of subtype selective antagonists suitable for in vivo evaluation. Depending on the species and/or vascular bed, each a1-adrenoceptor subtype can contribute to vascular contraction.
For example, contraction of the rat caudal artery is mediated by the a1A-adrenoceptor, the rat aorta by the a1D -adrenoceptor, and many canine and human vessels by the a1L -adrenoceptor (Muramatsu et al. 1998). Knockout of the a1B-adrenoceptor significantly attenuates the pressor response to a1-adrenoceptor agonists in the mouse. a2-Adrenoceptors within the CNS have long been known to be involved in the antihypertensive action of clonidine and other a2-adrenoceptor agonists (Timmermans et al. 1982). Although the involvement of a non-adrenergic imidazoline receptor in this action has been postulated (Ernsberger et al. 1990), the failure of a2-adrenoceptor agonists to produce a sympatholytic action in mice where the a2a-adrenoceptor has been knocked out or mutated (Hein et al. 1999) supports functional experiments in rats and rabbits suggesting an a2-adrenoceptor mediated action, at least for systemically administered agonists (Hieble and Kolpak 1993; Szabo et al. 1993; Urban et al. 1995). The hypertensive action of a2-adrenoceptor agonists likely results from activation ofvascular a2B-adrenoceptors (Hein etal. 1999). Consistent with the apparentrole of the a2B-adrenoceptor in the maintenance of vascular tone, mice lacking this receptor subtype failed to develop salt-induced hypertension (Makaritsis et al. 1999). Hence, a selective a2A-adrenoceptor agonist maybe preferable as a centrally active drug, although sedative and antihypertensive actions can apparently not be dissociated by subtype selectivity. Knockout of the a2c-adrenoceptor has no apparent cardiovascular effect. Recent data also indicate that the a2C-adrenoceptor participates in cold-induced augmentation of a-adrenoceptor mediated vasoconstriction (Chotani et al. 2000). Although multiple ^-adrenoceptor subtypes can participate in the cardiac stimulation produced by the catecholamines, gene knockout experiments demonstrate that the p1-adrenoceptor subtype plays the major role. Experimental evidence has been presented supporting the presence of an additional ^-adrenoceptor, tentatively designated as the p4-adrenoceptor, modulating cardiac contractility (Kaumann and Molenaar 1997). However, it now seems likely that these data may be explained by multiple affinity states ofthe p1-adrenoceptor (Oostendorp etal. 2000).
Mice lacking the p1 adrenoceptor fail to respond to the inotropic action of ^-adrenoceptor agonists, confirming the importance of this subtype in the control of cardiac contractility. However, maximal exercise capacity is not reduced (Rohrer etal. 1998). Mice lacking the p2-adrenoceptor have a normal response to exogenous ^-adrenoceptor agonists, and have even greater exercise capacity than wild-type mice. However, these animals become hypertensive during exercise and have a lower respiratory exchange ratio, suggesting influences of the p2-adrenoceptor on energy metabolism (Chruscinski etal. 1999). Mice lacking both p1- and ^-adrenoceptors have normalbasal cardiovascular parametres and normal exercise capacity, although the ability of exercise or the administration of exogenous agonists to increase heart rate is blunted (Rohrer et al. 1999). Mice lacking the p3-adrenoceptor show mild increases in body fat stores, and do not show metabolic responses to a selective p3-adrenoceptor agonists (Susulic et al. 1995). In several cases, an increased responsiveness to one of the remaining ^-adrenoceptors is observed when one of the subtypes is knocked out. Thus, there is increased p1-adrenoceptor responsiveness in p3-adrenoceptor knockout animals, and enhanced ^-adrenoceptor responsiveness in p1/p2 knockout animals. These observations support the concept that many physiological functions can be mediated by multiple P-adrenoceptor subtypes. Cardiac-directed overexpression of the human p1-adrenoceptor results in the accumulation offibrous tissue between cardiac myocytes, myocyte hypertrophy, and myofibrilar disarray (Bisognano etal. 2000). These changes result in cardiac dysfunction in older animals (Bisognano et al. 2000; Engelhardt et al. 1999). Overexpression of human P-adrenoceptors in mouse heart enhances basal cardiac function, due to constitutive activity of the expressed receptors (Liggett etal. 2000). Fibrotic cardiomyopathy is observed in mice expressing high levels of the ß2-adrenoceptor, with the severity and rate of onset being dependent on the level of receptor expression. Overexpression of cardiac ß2-adrenoceptors exacerbates functional deterioration following pressure overload as a result of aortic stenosis (Du etal. 2000).
Many important drugs target the ß-adrenoceptor. ß-Adrenoceptor antagonists, either selective or nonselective for the ßi-adrenoceptor, are widely used as antihypertensives. The mechanism for this action is still not clearly understood, but may involve, at least in part, an action on central ß-adrenoceptors or inhibition of renin release via the ß1-adrenoceptor. Several ß-adrenoceptor antagonists, including carvedilol, which combines nonselective ß-adrenoceptor blockade with a1-adrenoceptor blockade (Hieble et al. 1998), have been shown to produce a dramatic reductions in the mortality and morbidity associated with congestive heart failure (Nuttall et al. 2000). ß-Adrenoceptor antagonists have other cardiovascular applications, including the prevention and treatment of myocardial infarction, angina pectoris, and cardiac arrhythmia.
Bronchodilation is mediated primarily by the ß2-adrenoceptor. Selective overexpression of ß2-adrenoceptors in airway epithelium or smooth muscle results in decreased sensitivity to methacholine-induced bronchoconstriction (McGraw et al. 2000), and an increased sensitivity to a ß-adrenoceptor agonists. Selective ß2-adrenoceptor agonists are commonly used as bronchodilators in the treatment of asthma and other conditions associated with inappropriate bronchoconstriction. These agents are synergistic with inhaled steroids, and may have other beneficial actions, such as reduction of neutrophil infiltration (Howarth et al. 2000).
Contraction of prostatic and urethral smooth muscle appears to be mediated by the a1L-adrenoceptor. a1-adrenoceptor antagonists having selective affinity for a1A- and a1L-adrenoceptors, as well as antagonists having affinity for both a1A- and a1D-adrenoceptors, are currently being developed for the treatment of benign prostatic hyperplasia, although it has not yet been established that these drugs are clinically superior to the non-subtype selective a1-adrenoceptor antagonists which have been proven to be effective for this indication.
Intra-ocular administration of an a2-adrenoceptor agonist will reduce intra-ocular pressure in glaucoma as will intra-ocular administration of nonselective ß-adrenoceptor antagonists. None of the agonists employed clinically have pharmacologically significant selectivity between any of the a2-adrenoceptor subtypes. Selective ß3-adrenoceptor agonists are being developed for the treatment of type II diabetes and obesity. Although these agonists are clearly effective in animal models, and can produce metabolic effects in man (Weyer et al. 1998) clinical efficacy has been elusive. This is partially a result of pharmacological differences between rodent and human ß3-adrenoceptors (Sennitt et al. 1998) causing many compounds to have much lower efficacy at the human receptor. Knockout of the ß1-adrenoceptor has a marked effect on embryonic viability, although the few homozygous animals surviving appear normal (Rohrer et al. 1996). This effect on viability is not observed with knockout of the ß2- or ß3-adrenoceptor subtypes.
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