Negative inotropic effect of platelet-activating factor: association with a decrease in intracellular sodium activity.
Platelet-activating factor (PAF) is an autacoid whose cardiovascular actions include a potent negative inotropic effect. The mechanism of this decrease in myocardial contractility is still at issue, as both a decrease and an increase in trans-sarcolemmal Ca++ influx have been reported. Because changes in intracellular sodium activity (aiNa) are known to influence myocardial contractility, we investigated whether PAF affects aiNa. Thus, we have measured contractile responses to PAF (1 nM-1 microM) in isolated guinea pig right ventricular papillary muscles paced at constant rate, and recorded transmembrane action potential and aiNa with conventional and sodium-selective microelectrodes, respectively. Our findings suggest that PAF does not affect slow inward Ca++ current, because PAF neither affected nor prevented histamine-induced restoration of contractile responses in K+-depolarized papillary muscles. On the other hand, we found the negative inotropic effect of PAF to be associated with a shortening of the action potential duration and with a decrease in aiNa. The specific PAF antagonist compound CV-3988 inhibited all three electro-mechanical responses. Our findings imply that the decrease in contractile force caused by PAF may depend on the reduction in aiNa; as aiNa falls, intracellular Ca++ may be lost via the Na+/Ca++ exchange and contractility decreases. The shortening of the action potential duration by PAF may reflect a decrease in Na+ influx and the consequent reduction in aiNa.
Robertson
D A
DA
Department of Pharmacology, Cornell University Medical College, New York, New York.
Wang
D Y
DY
Lee
C O
CO
Levi
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R
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*
D010972:Platelet Activating Factor; D006632:Histamine; D012964:Sodium