Electrophysiological mechanisms responsible for the action of PAF in guinea-pig myocardium. Relation to the putative membrane signalling processes of PAF

Abstract

The effects of platelet-activating factor (PAF) on intracellular action potentials and isometric contractions of guinea-pig auricle muscle and ionic currents of frog atrial trabeculae were investigated. Experiments to study the effects of PAF on ionic currents in nerve fibre membrane were performed on frog single nodes of Ranvier. 10(-7) M PAF induced a negative inotropic effect accompanied by a decrease in amplitude, duration and upstroke velocity of the action potential without changes in the resting potential in guinea-pig auricle muscle. Wash-out of PAF restored the action potential parameters and contractile response after an initial transient positive inotropic effect. By contrast, 10(-10) M PAF exerted a transient positive inotropic effect followed by a negative one, while wash-out of PAF initiated a transient positive effect on inotropism, followed by recovery of contractile force. The slow action potentials and contractile responses were depressed by 10(-7) M PAF in a depolarizing K-rich solution. Histamine (10(-4) M) and 4-aminopyridine (3 mM) inhibited the depressant effects of PAF (10(-7) M) on the slow electromechanical responses. PAF (10(-7) M) reduced the peak of slow inward Ca current in frog atrial trabeculae. Simultaneously, the delayed outward K current was increased by PAF (10(-7) M). The present results point to a PAF-induced change in the ratio of sarcolemmal Ca and K conductance responsible for the negative inotropic action of PAF in guinea-pig myocardium which could result from a primary increase in K conductance. The specific PAF antagonist U-66985 (1-5 x 10(-6) M) was capable of inhibiting the PAF (10(-7) M)-induced negative effects on inotropism and action potentials implying membrane signalling coupled by specific binding sites for PAF in guinea-pig myocardium. Furthermore, pretreatment of the frog atrial trabeculae with BN 52021 (4 x 10(-6) M) nearly completely prevented the PAF (2 x 10(-7) M)-induced alterations in ionic currents. PAF (10(-10)-10(-6) M) was shown to selectively reduce the outward K current in nerve fibre membrane which we discussed in relation to a possible release of endogenous catecholamines proposed by Camussi et al. (1984) to be responsible for the positive inotropic action of PAF. However, the positive and negative inotropic action of PAF can be advantageously explained by the presence of two distinct PAF receptors in guinea-pig cardiac cells, one being linked to the IP3 pathway and the other to the cAMP pathway.