Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts.

Abstract

The aim of this study was to assess whether cyclooxygenase (COX) inhibitors protect the endothelial function against the deleterious effect of ischemia and reperfusion. Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow, 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619, and the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation to SNP was unaffected in all groups. Pretreatment with 6-MNA, 30 microM, a COX-2 inhibitor with some activity on COX 1, diclofenac, 1 microM (COX-1 and -2), or 1-(7-carboxyheptyl) imidazole, 10 microM [thromboxane (TX) synthase inhibitor] but not indomethacin, 10 microM (COX-1 inhibitor) preserved the vasodilation induced by 5-HT after ischemia. Enzyme immunoassays indicated that all COX inhibitors decreased the concentration of TXB2 and 6-keto-PGF1alpha [stable metabolites of TXA2 and prostacyclin (PGI2), respectively] in coronary effluent during ischemia. Furthermore, indomethacin was the only one to abolish the concentration of PGE2 during ischemia and early reperfusion. No clear trend on ventricular postischemic recovery could be observed between treated and untreated groups under our experimental protocols. These data suggest that, under our conditions, 6-MNA, diclofenac, and 1-7-CHI, but not indomethacin, protect the endothelial function via a reduction in TX concentration. Disparities between COX inhibitors may be due to the complete abolition of PGE2 concentration during ischemia and reperfusion in the indomethacin group.

• Authors: J F Bouchard, D Lamontagne
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 34 Issue 5 Pg. 755-63 (Nov 1999) ISSN: 0160-2446 [Print] United States
• PMID: 10547094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Cyclooxygenase Inhibitors
• Imidazoles
• Diclofenac
• Arachidonic Acid
• 1-(7-carboxyhexyl)imidazole
• Indomethacin

Topics

• Animals
• Arachidonic Acid (metabolism)
• Cardiotonic Agents (therapeutic use)
• Coronary Circulation (drug effects)
• Coronary Vessels (drug effects, physiology)
• Cyclooxygenase Inhibitors (therapeutic use)
• Diclofenac (therapeutic use)
• Endothelium, Vascular (drug effects, physiopathology)
• Imidazoles (pharmacology)
• In Vitro Techniques
• Indomethacin (pharmacology)
• Male
• Myocardial Ischemia (prevention & control)
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Vascular Resistance (drug effects)