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

Abstract

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.

• Authors: G K Oriji
• Journal: Prostaglandins, leukotrienes, and essential fatty acids (Prostaglandins Leukot Essent Fatty Acids) Vol. 63 Issue 6 Pg. 343-9 (Dec 2000) ISSN: 0952-3278 [Print] Scotland
• PMID: 11133171 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Prostaglandin Antagonists
• Vasodilator Agents
• Phorbol 12,13-Dibutyrate
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Epoprostenol
• Protein Kinase C
• Adenosine
• Indomethacin

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (pharmacology)
• Adenosine (pharmacology)
• Animals
• Depression, Chemical
• Drug Interactions
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Epoprostenol (physiology)
• Heart Rate (drug effects)
• Indomethacin (pharmacology)
• Male
• Myocardial Contraction (drug effects)
• Myocardial Ischemia (metabolism)
• Perfusion
• Phorbol 12,13-Dibutyrate (pharmacology)
• Prostaglandin Antagonists (pharmacology)
• Protein Kinase C (antagonists & inhibitors, physiology)
• Rats
• Vasodilator Agents (pharmacology)