Species-specific pharmacological properties of human alpha(2A)-adrenoceptors

On the basis of data obtained in rabbits, the imidazoline receptor ligand r ilmenidine has been suggested to decrease blood pressure in humans by activ ating central alpha(2A)-adrenoceptors. A prerequisite for this hypothesis w as the unproved assumption that rabbit and human alpha(2A)-adrenoceptors ar e equally activated by rilmenidine. Because alpha(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 assu mption. Human atrial appendages and rabbit pulmonary arteries were used to determine the potencies of alpha(2)-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked [H-3]norepinephrine release and of antagonists in counteracting the alpha(2)-adrenoceptor-mediated inhibition induced by m oxonidine. In the rabbit pulmonary artery, rilmenidine and oxymetazoline ar e potent full agonists, whereas in the human atrial appendages they are ant agonists at the alpha(2)-autoreceptors, sharing this property with rauwolsc ine, phentolamine, and idazoxan. In contrast, prazosin is ineffective. In a ddition, a partial nucleotide and amino acid sequence of the rabbit alpha(2 A)-adrenoceptor (a region known to substantially influence the pharmacologi cal characteristics of the alpha(2)-adrenoceptor) revealed marked differenc es between the rabbit and the human alpha(2A)-adrenoceptor. The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with a,,autoreceptors, at which, however, both rilmenidine and oxy metazoline exhibit different properties (antagonism and agonism, respective ly). The antagonistic property of rilmenidine at human alpha(2A)-adrenocept ors 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 alph a(2A)-adrenoceptors but other, presumably I-1-imidazoline receptors, are pr obably involved.