Pre- and postjunctional alpha-adrenoceptor-mediated effects of prazosin, methoxamine and 6-fluoronoradrenaline in blood-perfused canine skeletal muscle in situ.

Abstract

Pre- and postjunctional effects of the alpha 1-selective adrenoceptor antagonist prazosin and the alpha 1- and alpha 2-selective adrenoceptor agonists methoxamine and 6-fluoronoradrenaline, respectively, were studied in skeletal muscle in situ. Prazosin reduced the vasoconstriction and enhanced the overflow of endogenous noradrenaline elicited by sympathetic nerve stimulation (1-4 Hz, 2 min); the threshold concentration was 10-100 times lower for postjunctional than for prejunctional alpha-adrenoceptor blockade. The enhancement of noradrenaline overflow by prazosin was not inversely frequency-dependent, as shown elsewhere for alpha 2-adrenoceptor antagonists. Thus, different mechanisms may be involved. Inhibition of prostaglandin synthesis by diclofenac did not alter the stimulation-evoked noradrenaline overflow, indicating a minor importance of prostaglandin-mediated transjunctional mechanisms in the modulation of noradrenaline overflow. Methoxamine and 6-fluoronoradrenaline elevated the basal vascular tone and, at higher concentrations, reduced the stimulation-evoked noradrenaline overflow. Methoxamine was 20 times more selective than 6-fluoronoradrenaline for postjunctional receptors. Our results are compatible with a pre- and postjunctional localization of alpha 2-adrenoceptors and a predominantly, but not exclusively, postjunctional localization of alpha 1-adrenoceptors. The postjunctional selectivity for prazosin was less marked than previously reported from in vitro studies. Hence, care should be taken when extrapolating in vitro findings to the more complex in vivo situation.