An evaluation of the alpha-adrenoceptor antagonism produced by SK&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.
Schafers
R F
RF
University Department of Medicine and Therapeutics, Stobhill General Hospital, Glasgow.
Elliott
H L
HL
Howie
C A
CA
Reid
J L
JL
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000097:blood; D011311:Pressoreceptors / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D009638:Norepinephrine; C039139:benalfocin