Journal
ZEITSCHRIFT FUR KARDIOLOGIE
Volume 90, Issue 9, Pages 607-612Publisher
DR DIETRICH STEINKOPFF VERLAG
DOI: 10.1007/s003920170107
Keywords
alpha(2)-adrenergic receptors; transgenic mouse; knockout mouse; presynaptic receptors; sympathetic nervous system
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The adrenergic System plays an essential role in the regulation of cardiovascular homeostasis. The endogenous catecholamines adrenaline and noradrenaline mediate their biological actions via activation of nine different adrenergic receptor subtypes, three alpha (1)-receptors (alpha (1A), alpha (1B), alpha (1D)), three alpha (2)-receptors (alpha (2A), alpha (2B), alpha (2C)) and three beta -receptors (beta (1), beta (2), beta (3)). Only a few subtype-selective ligands exist which can be used to determine the physiological and pathophysiological significance of these individual receptor subtypes. Recent progress in mouse molecular genetics has led to the generation of transgenic models carrying deletions in individual adrenergic receptor genes (knockout mice). These mouse models were used to determine the specific functions of the three alpha (2)-receptor subtypes. alpha (2A)-receptors mediate the central antihypertensive action of the alpha (2)-agonists, clonidine and moxonidine. Stimulation of vascular alpha (2B)-receptors causes a transient vasoconstriction. The release of noradrenaline from sympathetic nerves is controlled by presynaptic alpha (2A)- and alpha (2C)-receptors. Both presynaptic alpha (2)-receptors are essential, as deletion of alpha (2A)- and alpha (2C)-receptors leads to cardiac hypertrophy and failure due to chronically enhanced catecholamine release. These studies demonstrate the power of mouse molecular genetics to determine the physiological significance of adrenergic receptor subtype diversity and point out novel strategies for subtype-selective drug development.
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