Peripheral pre and postjunctional alpha 2-adrenoceptors in man: studies with RX781094, a selective alpha 2 antagonist

The imidazoline derivative RX781094 has been shown in animal studies to be a potent selective alpha 2-adrenoceptor antagonist. The alpha 2 antagonist activity of RX781094 was confirmed in this study by in vitro human platelet aggregation studies in which RX781094 was five times more potent than alpha-yohimbine. Within the first 20 min after intravenous administration of RX781094 to eight normotensive men there was a short-lived increase in blood pressure (mean maximum change 9/7 mmHg) and decrease in heart rate (mean maximum change 15 beats/min) associated with slight increases in plasma noradrenaline concentration and renin activity. These findings are consistent with an effect at prejunctional alpha 2-adrenoceptors. The pressor dose-response analysis for three agonists of varying selectivities for alpha 1 and alpha 2-adrenoceptors showed only modest changes with phenylephrine and noradrenaline with dose ratios less than 2, in contrast to the marked antagonism by RX781094 of the pressor response to the alpha 2 agonist, alphamethylnoradrenaline, dose ratio greater than 20. These results provide evidence that adrenoceptors of the alpha 2 subtype are located postjunctionally on resistance vessels in man and that RX781094 is a selective antagonist at human alpha 2-adrenoceptors.