alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Researchers' studies have shown that /sup 3/H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, /sup 3/H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but /sup 3/H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.
1. The combined use of alpha-methyldopa and L-alpha-methyldopa hydrazine (a peripheral decarboxylase inhibitor) has been studied, in a double-blind cross-over comparison, with alpha-methyldopa and L-alpha-methyldopa hydrazine placebo in the treatment of eight patients with essential hypertension. 2. L-alpha-methyldopa hydrazine did not enhance the antihypertensive effect of alpha-methyldopa. This suggests that because methyldopa can inhibit its own decarboxylation, peripheral decarboxylation is not an important metabolic pathway for methyldopa and elevated brain levels of methyldopa do not necessarily result in elevated brain levels of methyldopamine.
Summary: The α1- and α2-adrenoreceptor types are defined in terms of the selective binding of radioligands and their displacement from membrane preparations by a range of agonists and antagonists. Their distribution is described in brain, kidney, heart, and peripheral blood vessels. A group of centrally acting clonidine-like drugs are classified in terms of their selectivity for the α2-adrenoreceptors, and it is suggested that differences between α-adrenoreceptors in various tissues may allow development of highly selective α2-adrenoreceptor agonists for specific tissue sites such as the juxtaglomerular cells and brainstem nuclei controlling blood pressure. It is further suggested that the aim of treatment with such compounds is to modulate adrenergic activity while retaining normal homeostatic mechanisms. For this purpose, competitive agonists and antagonists are preferable to compounds which bind irreversibly to the receptor.
Summary: Central and peripheral α-adrenoceptors play an important role in cardiovascular regulation, and selective α1-adrenoceptor antagonists and α2-adrenoceptor agonists have an established place in the therapy of hypertension. Prazosin is a selective α1-antagonist that is both effective in lowering blood pressure and well tolerated. However, the more recently developed α1-antagonists doxazosin and terazosin offer the advantage of having longer half-lives, allowing once daily administration. Clonidine is a centrally acting α2-agonist whose clinical use has often been limited by the dose dependent side effects of dry mouth and sedation, and the belief that it should be given three times per day. However, recent studies have shown that it has substantial antihypertensive efficacy with minimal side effects at low doses, and that half-life is long enough to allow twice daily administration. An improved understanding of the pharmacodynamics and pharmacokinetics of drugs acting on α-adrenoceptors allows a more rational approach to their clinical application.
Studies using a sensitive radioenzymatic assay for plasma noradrenaline suggest there is a selective overactivity of the sympathetic nervous system in essential hypertension. Methodology which allows the study of local sympathetic turnover in CNS nuclei and peripheral blood vessels is described. This approach has been used to study the non-innervated sympathetic turnover phaeochromocytoma. It is suggested that studies of local regulatory mechanism in neurotransmitter release are required to give a greater understanding of the central and peripheral role of the sympathetic nervous system in the pathogenesis of hypertension.
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