Active transport and inotropic state in guinea pig left atrium

Abstract

Although the positive inotropic effect of cardiac glycosides correlates well with inhibition of Na+ pump activity in many preparations, digitalis at low concentrations (10(-9) to 10(-8) M) may produce an apparent stimulation of monovalent cation transport in isolated intact myocardium or produce an inotropic effect that does not correlate with pump inhibition. Digitalis is known to modify tissue metabolism of endogenous neurotransmitters that may affect inotropic state, Na,K-ATPase activity, and K+ permeability. We examined the interactions of low concentrations of ouabain with adrenergic and cholinergic influences in isolated guinea pig left atria stimulated at 3.3 Hz in which inotropic state and monovalent cation transport (measured as 86Rb+ uptake) were assessed simultaneously. Ouabain (10(-9) M) stimulated Rb+ transport (+25%) without an inotropic response; the stimulatory effect on transport was abolished by propranolol or atropine pretreatment. In atria pretreated with atropine, 10(-8) M ouabain produced a small positive inotropic effect (+10%) without measurable associated Na+-K+ pump inhibition. This inotropic response was abolished in catecholamine-depleted atria. Ouabain (10(-7) M) always produced a positive inotropic response (about +25%) independent of catecholamine depletion, beta-adrenergic blockade, or muscarinic blockade, but Rb+ uptake inhibition was observed only in beta-adrenergically-blocked atria. In all preparations, ouabain concentrations greater than 10(-7) M caused an inotropic response associated with pump inhibition. At concentrations 3 X 10(-7) M and higher, mechanical toxicity was observed in all preparations except those pretreated with propranolol. Incubation with low concentrations of ouabain did not modify the inotropic response to isoproterenol. At concentrations of isoproterenol sufficient to stimulate Rb+ transport by 25%, there was a large (+80%) inotropic response. We conclude first, that, in guinea pig atria exposed to ouabain, the mechanism as well as the extent of inotropic response and of monovalent cation transport modification is concentration dependent, second, that at low concentrations (1-10 X 10(-9) M), in vitro inotropic and monovalent cation transport responses are in part mediated by an effect of ouabain on endogenous neurotransmitters; and third, that in this preparation at concentrations between 10(-9) and 10(-7) M ouabain, monovalent cation transport as measured by tissue 86Rb+ uptake does not correlate with inotropic response.