Blockade by nifedipine of responses to intravenous bolus injection or infusion of alpha 1- and alpha 2-adrenoceptor agonists in the pithed rat

Abstract

Nifedipine was tested against pressor responses in the pithed rat to ten agonists with varying selectivity for alpha 1- and alpha 2-adrenoceptors, injected as a bolus or infused intravenously: i.e. amidephrine, azepexole, cirazoline, indanidine, M7, methoxamine, noradrenaline (NA), oxymetazoline, phenylephrine and xylazine. Nifedipine, administered before the agonists, inhibited responses initiated by all agonists, usually for both the bolus and infusion responses. With a bolus, blockade was significantly greater against the more prolonged, secondary components of the pressor responses. This demonstrates that calcium-entry occurs during the secondary component of the alpha-adrenoceptor-mediated response and can be initiated by either alpha 1- or alpha 2-adrenoceptor subtypes. The time courses of responses to infusion varied. Selective alpha 1-adrenoceptor agonists, with the exception of indanidine, did not produce a stable pressor response during the 20 min infusion time but alpha 2-adrenoceptor agonists did. Nifedipine reduced responses to infusion with no preference for alpha 1- or alpha 2-agonists. Phenylephrine and NA produced pressor responses which reached a peak and then declined during the remainder of the infusion. The levels of NA in arterial and venous plasma were measured by h.p.l.c. during the infusion of NA. Arterial NA levels rose throughout the infusion whereas venous levels remained relatively unaffected. The absolute levels of plasma NA suggest that a large proportion of intravenously administered NA is removed in the pulmonary circulation and the remainder is removed in the systemic circulation with negligible recirculation. The consequences of these results, for assessment of the mechanisms of action of adrenoceptor agonists and calcium entry blockers, are discussed.