Receptor Subtypes As Novel Targets

Adrenoceptors constitute an established family of therapeutic drug targets and demonstrate how accumulating knowledge of receptor subtypes has gradually led to more refined therapeutic approaches in cardiovascular diseases. Mammals have nine subtypes of adrenoceptors. Norepinephrine, the sympathetic neurotransmitter, and epinephrine, an adrenomedullary hormone, regulate cardiovascular functions through most, or perhaps even all of these subtypes.

The first division of adrenoceptors into two classes was based on the potency of a series of catecholamine derivatives to elicit functional responses in vascular and other smooth muscles and in the heart.10 a-Adrenoceptor activation elicited contraction of vascular smooth muscle and had little effect on the heart, while p-adreno-ceptor activation had positive inotropic and chronotropic effects on the heart and relaxed smooth muscle tissues. Further pharmacological adrenoceptor classifications allowed a distinction between ^-adrenoceptors predominantly responsible for cardiac stimulation and p2-adrenoceptors that mediate relaxation of vascular and bronchial smooth muscles.11 This distinction allowed the development of selective p1-adrenoceptor antagonists for hypertension and other cardiovascular indications and selective p2-adrenoceptor agonists for the symptomatic treatment of asthma.

The first subdivision of the a-adrenoceptors into a1- and a2-adrenoceptor subtypes was based largely on different functions and anatomical locations.1213 Pre-synaptic a-adrenoceptors regulating neurotransmitter release were termed a2-adrenoceptors, whereas postjunctional a-receptors were referred to as a1-adreno-ceptors. Further pharmacological experiments revealed that a2-adrenoceptors are located both pre- and postsynaptically and that they mediate a complex spectrum of pharmacological actions.1415 A pharmacological a-adrenoceptor classification was based on actions of selective agonists and antagonists. a1-Adrenoceptors can be activated by phenylephrine and blocked by low concentrations of prazosin, whereas a2-adrenoceptors can be activated by clonidine and blocked by low concentrations of yohimbine.1617 The current adrenoceptor classification is based on molecular cloning of the nine distinct mammalian genes encoding three a1-, three a2- and three p-adrenoceptor subtypes.

a1-Adrenoceptors regulate many physiological processes, including smooth muscle tone (vascular and other), myocardial inotropy, and hepatic glucose metabolism. The a1A-adrenoceptor subtype is the predominant a1-adrenoceptor in the heart and in arterial smooth muscle; a1B-adrenoceptors mediate vasoconstriction and elevation of blood pressure.18 Subtype-nonselective a1-adrenoceptor agonists (such as phenylephrine) and antagonists (such as prazosin) have been used in cardiovascular therapeutics, but have been largely replaced by new drugs with other mechanisms of action and better tolerability.

The a2-adrenoceptors mediate a number of physiological and pharmacological responses such as hypotension, sedation, inhibition of insulin release, inhibition of lipolysis, and platelet aggregation.5 In contrast to the Gs-coupled p-adrenoceptors and the Gq-coupled a1-adrenoceptors, the a2-adrenoceptors preferentially couple to the Gi/Go family of heterotrimeric guanine nucleotide binding proteins and thereby regulate a variety of effector systems including adenylyl cyclases19 and K+ and Ca++ channels.20

The a2A-adrenoceptor is the principal presynaptic inhibitory autoreceptor regulating synaptic release of norepinephrine from central and peripheral sympathetic nerves. This receptor subtype is highly expressed in the brain stem and is abundantly distributed throughout the central nervous system and several peripheral tissues.21-23 The a2A-adrenoceptor is directly involved in the control of sympathetic outflow, its activation resulting in reduction of blood pressure and heart rate. Actually, most of the classical pharmacological actions in response to a2-adrenoceptor agonists are now ascribed to the a2A-adrenoceptor subtype. These effects include the sedative, antinoci-ceptive, anesthetic, hypothermic, hypotensive, and bradycardic effects of clonidine and related drugs.524 Compared to wild-type control mice, mice genetically engineered to lack a2A-adrenoceptors exhibit higher resting systemic blood pressure and heart rates that correlate with increased norepinephrine release from cardiac sympathetic nerves.

Expression of the a2B-adrenoceptor subtype in brain is restricted to the thalamus and nucleus of the solitary tract in the brain stem.212325 Abundant expression of this subtype is seen in rat vascular smooth muscle cells26 and in human and rat kidney.2127 This subtype appears to exert a critical role in the peripheral vasoconstrictor action of a2-adrenoceptor agonists. Contrary to what was observed in normal control mice, intravenous administration of an a2-adrenoceptor agonist to a2B-adrenoceptor knockout mice failed to elicit the initial transient increase in blood pressure.6

This receptor subtype has also been found to play a dominant role in salt-induced experimental hypertension. Indeed, mice with deletion of only one copy of the a2B-adrenoceptor gene were unable to develop hypertension in response to dietary salt loading, indicating that a full complement of a2B-adrenoceptor genes is necessary to raise blood pressure in response to dietary salt loading.28 It is not yet known whether this role of a2B-adrenoceptors is dependent on vascular responsiveness, on renal ability to retain sodium and water, on presynaptic regulation of norepinephrine release, or on central neuronal mechanisms.

The physiological roles of a2C-adrenoceptors are less known. It was recently shown that a2C-adrenoceptors mediate presynaptic inhibition of norepinephrine release. The a2C-adrenoceptor subtype inhibits neurotransmitter release at low stimulation frequencies, whereas the a2A-adrenoceptor subtype regulates release at high stimulation frequencies, and regulation in both frequency ranges is physiologically important.2930 A very interesting recent finding in this context was that mice with targeted inactivation of the a2C-adrenoceptor gene were more prone to develop congestive heart failure upon aortic banding than control mice. Also, a2A-adreno-ceptor gene knock-out sensitized the mice to this form of heart failure induced by increased workload and sympathetic overactivity, and the combined deletion of both the a2A- and the a2C-adrenoceptor subtypes resulted in rapid deterioration in cardiac function and high mortality after aortic banding.31

Identification of the physiological functions of the individual a2-adrenoceptor subtypes and the subsequent availability of genetically modified mouse lines have provided further opportunities for the development and evaluation of new therapeu-tically useful subtype-selective agonists and antagonists.

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