Adenosine acts as a
cardioprotective agent by producing coronary vasodilation, 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
adenosine, increased
protein kinase C (PKC) activity and
prostacyclin (PGI2) release. The present study was conducted to determine if
myocardial ischemia alters the cardioprotective effect of
adenosine by increasing PKC activity and PGI2 release in the isolated rat heart perfused
at 10 ml/min with
Krebs-Henseleit buffer (KHB; 95% O2+5% CO2).
Adenosine (10 mmol/min) reduced myocardial contractility as indicated by a decrease in contractility (dp/dtmax), heart rate (HR) and coronary perfusion pressure (PP). In hearts subjected to 30 min of
ischemia (without perfusion) and then reperfused with KHB,
adenosine failed to decrease dp/dtmax, HR or PP. However, during infusion of PKC inhibitor
H-7 (1-(5-Isoquinolinesulfonyl)-2-methylpiperazine hydrochloride) (
H-7; 6 mmol/min), which commenced 10 min before
ischemia and continued throughout reperfusion,
adenosine produced a decrease in dp/dtmax, HR and PP, similar to that before
ischemia. Infusion of the PKC activator
phorbol 12,13-dibutyrate (PDBu; 2 nmol/min) but not an inactive analogue in non-ischemic hearts prevented the
adenosine induced decrease in dp/dtmax. During infusion of
H-7, PDBu failed to block the direct negative inotropic effect of
adenosine in non-ischemic hearts. In addition, pretreatment with
H-7 or
indomethacin (
cyclooxygenase inhibitor) significantly reduced the PGI2 release following
ischemia. This data suggest that PKC and PGI2 regulate the direct negative inotropic effect of
adenosine, which is abolished during
ischemia.