Adenosine induced direct negative inotropic effect is abolished during global ischemia: role of protein kinase C and prostacyclin

Adenosine acts as a cardioprotective agent by producing coronary vasodilati on, decreasing heart rate and by antagonizing the cardiostimulatory effect of catecholamines; adenosine also exerts a direct negative inotropic effect . Myocardial ischemia is known to be associated with enhanced levels of ade nosine, increased protein kinase C (PKC) activity and prostacyclin (PGI(2)) release. The present study was conducted to determine if myocardial ischem ia alters the cardioprotective effect of adenosine by increasing PKC activi ty and PGI(2) release in the isolated rat heart perfused at 10 ml/min with Krebs-Henseleit buffer (KHB; 95% O-2+5% CO2). Adenosine (10 mmol/min) reduc ed myocardial contractility as indicated by a decrease in contractility (dp /dt(max)), heart rate (HR) and coronary perfusion pressure (PP). In hearts subjected to 30 min of ischemia (without perfusion) and then reperfused wit h KHB, adenosine failed to decrease dp/dt(max), HR or PP. however, during i nfusion of PKC inhibitor H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride) (H-7; 6 mmol/min), which commenced 10 min before ischemia a nd continued throughout reperfusion, adenosine produced a decrease in dp/dt (max), HR and PP, similar to that before ischemia. Infusion of the PKC acti vator phorbol 12;13-dibutyrate (PDBu; 2 nmol/min) but not an inactive analo gue in non-ischemic hearts prevented the adenosine induced decrease in dp/d t(max). During infusion of H-7, PDBu failed to block the direct negative in otropic effect of adenosine in non-ischemic hearts. In addition, pretreatme nt with H-7 or indomethacin (cyclooxygenase inhibitor) significantly reduce d the PGI(2) release following ischemia. This data suggest that PKC and PGI (2) regulate the direct negative inotropic effect of adenosine, which is ab olished during ischemia. (C) 2000 Harcourt Publishers Ltd.