Gk. Oriji, Adenosine induced direct negative inotropic effect is abolished during global ischemia: role of protein kinase C and prostacyclin, PROS LEUK E, 63(6), 2000, pp. 343-349
Citations number
24
Categorie Soggetti
Cell & Developmental Biology
Journal title
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS
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.