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(Hypertension. 2000;36:405.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Species-Specific Pharmacological Properties of Human _2A-Adrenoceptors

Gerhard J. Molderings; Heinz Bönisch; Michael Brüss; James Likungu; Manfred Göthert

From Institut für Pharmakologie und Toxikologie, Universität Bonn (G.J.M., H.B., M.G.), and Klinik für Herz- und Gefäßchirurgie (J.L.), Bonn, Germany.

Correspondence to Gerhard J. Molderings, Institute of Pharmacology and Toxicology, University of Bonn, Reuterstr 2b, D-53113 Bonn, Germany. E-mail molderings{at}uni-bonn.de

Abstract—On the basis of data obtained in rabbits, the imidazoline receptor ligand rilmenidine has been suggested to decrease blood pressure in humans by activating central _2A-adrenoceptors. A prerequisite for this hypothesis was the unproved assumption that rabbit and human _2A-adrenoceptors are equally activated by rilmenidine. Because _2A-adrenoceptors in the brain and on cardiovascular sympathetic nerve terminals are identical, the latter were used as a model for the former to confirm or disprove this assumption. Human atrial appendages and rabbit pulmonary arteries were used to determine the potencies of ₂-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked [³H]norepinephrine release and of antagonists in counteracting the ₂-adrenoceptor–mediated inhibition induced by moxonidine. In the rabbit pulmonary artery, rilmenidine and oxymetazoline are potent full agonists, whereas in the human atrial appendages they are antagonists at the ₂-autoreceptors, sharing this property with rauwolscine, phentolamine, and idazoxan. In contrast, prazosin is ineffective. In addition, a partial nucleotide and amino acid sequence of the rabbit _2A-adrenoceptor (a region known to substantially influence the pharmacological characteristics of the ₂-adrenoceptor) revealed marked differences between the rabbit and the human _2A-adrenoceptor. The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with _2A-autoreceptors, at which, however, both rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively). The antagonistic property of rilmenidine at human _2A-adrenoceptors indicates that in contrast to the suggestion based on rabbit data, the hypotensive property of the drug in humans is not due to activation of _2A-adrenoceptors but other, presumably I₁-imidazoline receptors, are probably involved.

Key Words: receptors, adrenergic, alpha • human • norepinephrine • rabbits • rilmenidine

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