Alinidine reverses the descending staircase of isolated rat atria by an antimuscarinic action

Abstract

Contractile force of isolated atria from most mammalian species increases with the rate of electrical stimulation, resulting in an ascending staircase. In contrast, in the rat, contractile force decreases with increasing rate of stimulation (descending staircase). The bradycardic and antianginal drug alinidine (5.7-91.2 mumol/l) reversed the descending staircase to ascending by a positive inotropic effect at higher stimulation rates. Maximal positive inotropy was obtained with 45.6 mumol/l, a concentration which also caused maximal bradycardia in spontaneously beating atria. Concentrations of 1 mumol/l of the antimuscarinic compounds atropine as well as the quaternary salt ipratropium bromide also reversed the descending staircase of rat atria. Addition of alinidine did not cause any further increase in force of contraction under these conditions. Addition of 1 mumol/l physostigmine to isolated left atria from guinea pigs for blockade of acetylcholinesterase decreased contractility at all stimulation rates, but did not change the ascending character of the staircase. Alinidine antagonized the negative inotropic effect of physostigmine. The known antimuscarinic action of alinidine was quantified in electrically driven (0.25 Hz) left rat atria by antagonism of the negative inotropic effect of oxotremorine (0.01-10 mumol/l). Alinidine acted as a strictly competitive antagonist with a pA2 of 5.82. In isolated papillary muscle from guinea pigs, pretreated with reserpine for depletion of catecholamines, carbachol (0.1-3000 mumol/l) exerted positive inotropic effects. Alinidine antagonized also this effect in a competitive fashion with a pA2 value of 5.58.(ABSTRACT TRUNCATED AT 250 WORDS)