AN EVALUATION OF THE ALPHA-ADRENOCEPTOR ANTAGONISM PRODUCED BY SK-AND-F 86466 IN HEALTHY NORMOTENSIVE MALES

SK&F 86466 is a novel, potent alpha‐adrenoceptor antagonist which, in animal experiments, is reported to show a high selectivity for alpha 2‐ adrenoceptors at both pre‐ and post‐junctional sites. The effects of two intravenous doses of 80 and 200 micrograms kg‐1 of SK&F 86466 were assessed in a placebo‐controlled, double‐blind, randomised study in eight young, healthy, normotensive males. Two indices of alpha‐ adrenoceptor activity were investigated: i) Pressor responsiveness to the relatively selective alpha 1‐adrenoceptor agonist phenylephrine and to the preferential alpha 2‐adrenoceptor agonist alpha‐ methylnoradrenaline. ii) Circulating levels of noradrenaline. SK&F 86466 at a dose of 200 micrograms kg‐1 produced rightward shifts of the pressor dose‐response curves to both agonists: a 1.4 fold shift for phenylephrine (P = 0.023) and a 1.6 fold shift for alpha‐ methylnoradrenaline (P = 0.051). Erect plasma noradrenaline sampled at 105 min into the infusion was significantly increased from 2.9 to 5.0 nmol l‐1 by SK&F 86466 200 micrograms kg‐1 (P = 0.002). The change in the phenylephrine responses indicates post‐junctional alpha 1‐ adrenoceptor blockade and the rise in noradrenaline is consistent with pre‐junctional alpha 2‐adrenoceptor antagonist activity. Overall the results of this study suggest that SK&F 86466, at a dose of 200 micrograms kg‐1, causes both alpha 1‐ and alpha 2‐adrenoceptor antagonism in human subjects. 1990 The British Pharmacological Society