Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart.

Abstract

We have proposed that ischemic preconditioning in rabbit hearts is initiated by adenosine receptor stimulation resulting in activation of protein kinase C. If this theory is correct then any agonist which can activate PKC should also put the heart into a preconditioned state. This study sought to determine whether endothelin-1 (ET-1), which is known to activate protein kinase C can also mimic ischemic preconditioning. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 min reperfusion reduced infarct size to 5.6 +/- 0.7% (P < 0.01). Perfusion with either 10 PM ET-1 at constant coronary artery flow for 5 min in lieu of ischemia or 50 PM ET-1 with 10 nM nicardipine to block the former's coronary constructive effect was quite protective and equipotent with preconditioning. Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1.7% of the risk zone, respectively. This protection could be blocked by PD 156 707 (10 microM), a highly specific endothelin receptor antagonist. Chelerythrine (5 microM), a PKC inhibitor, also aborted protection (22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 microM), an adenosine receptor blocker, given during ET-1 administration did not block ET-1's protective effect indicating that adenosine was not involved in the effect. PD 156707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing that endothelin is not an important physiological mediator of ischemic preconditioning. We conclude that ET-1 can mimic ischemic preconditioning in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning.

• Authors: P Wang, K P Gallagher, J M Downey, M V Cohen
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 28 Issue 3 Pg. 579-88 (Mar 1996) ISSN: 0022-2828 [Print] England
• PMID: 9011641 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Benzophenanthridines
• Dioxoles
• Endothelin Receptor Antagonists
• Endothelin-1
• PD 156707
• Phenanthridines
• Purinergic P1 Receptor Antagonists
• Receptors, Endothelin
• 8-(4-sulfophenyl)theophylline
• Theophylline
• chelerythrine
• Protein Kinase C

Topics

• Alkaloids
• Animals
• Benzophenanthridines
• Coronary Vessels (drug effects, physiopathology)
• Dioxoles (pharmacology)
• Endothelin Receptor Antagonists
• Endothelin-1 (pharmacology, physiology)
• Female
• Heart (drug effects)
• Hemodynamics
• In Vitro Techniques
• Ischemic Preconditioning, Myocardial
• Male
• Myocardial Infarction (prevention & control)
• Phenanthridines (pharmacology)
• Protein Kinase C (antagonists & inhibitors)
• Purinergic P1 Receptor Antagonists
• Rabbits
• Receptors, Endothelin (metabolism)
• Theophylline (analogs & derivatives, pharmacology)