Species-Specific Pharmacological Properties of Human a2A-Adrenoceptors

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 a2A-adrenoceptors. A prerequisite for this hypothesis was the unproved assumption that rabbit and human a2A-adrenoceptors are equally activated by rilmenidine. Because a2A-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 a2-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked [H]norepinephrine release and of antagonists in counteracting the a2-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 a2-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 a2A-adrenoceptor (a region known to substantially influence the pharmacological characteristics of the a2-adrenoceptor) revealed marked differences between the rabbit and the human a2A-adrenoceptor. The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with a2Aautoreceptors, at which, however, both rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively). The antagonistic property of rilmenidine at human a2A-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 a2A-adrenoceptors but other, presumably I1-imidazoline receptors, are probably involved. (Hypertension. 2000;36:405-410.)