Postischemic antiarrhythmic effects of angiotensin-converting enzyme inhibitors. Role of suppression of endogenous endothelin secretion.

Abstract

BACKGROUND:

ACE inhibitors improve reperfusion function in several animal models. We tested the hypothesis that ACE inhibitor-induced coronary protection and inhibition of reperfusion arrhythmias are mediated by suppression of cardiac endothelin-1 (ET-1) secretion and action.

METHODS AND RESULTS:

The effects of two ACE inhibitors on ET-1 secretion and mechanical function during ischemia and reperfusion were studied in perfused rat hearts. Drugs were infused during the control (60 minutes), ischemic (60 minutes), and reperfusion (30 minutes) period. ET-1 appearing in coronary effluents and the interstitium was analyzed by radioimmunoassay. We observed (1) in hearts treated with ramiprilat (100 nmol/L) or captopril (5 mumol/L), a significant reduction of ET-1 secretion under all three experimental conditions and fewer ventricular extrasystoles during reperfusion; (2) increased ET-1 secretion and numerous tachyarrhythmic events in the presence of ACE inhibitor and a bradykinin B2 receptor antagonist, icatibant (100 nmol/L); (3) an almost-complete suppression of reperfusion arrhythmias when an ET receptor antagonist, ie, SB 209670 (5 mumol/L) or PD 142893 (200 nmol/L), was infused together with ACE inhibitor and icatibant; and (4) SB 209670 alone to be equally antiarrhythmic as ACE inhibitors. Exogenous ET-1 (40 pmol/L) was proarrhythmic, whereas exogenous bradykinin (100 nmol/L) reduced ET-1 secretion and improved cardiac rhythm.

CONCLUSIONS:

ACE inhibitors suppress endogenous ET-1 secretion, which results in improved coronary function and stabilization of cardiac rhythm after ischemia in this model. Suppression of ET-1 results from both removal of endogenous angiotensin II and accumulation of endogenous bradykinin/nitric oxide. ET receptor antagonists may be prime antiarrhythmic drugs worthy of testing in cardiac patients, either alone or together with ACE inhibitors.

• Authors: F Brunner, W R Kukovetz
• Journal: Circulation (Circulation) Vol. 94 Issue 7 Pg. 1752-61 (Oct 01 1996) ISSN: 0009-7322 [Print] United States
• PMID: 8840871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Anti-Arrhythmia Agents
• Bradykinin Receptor Antagonists
• Endothelin Receptor Antagonists
• Endothelins
• Angiotensin II
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase
• Bradykinin

Topics

• Angiotensin II (pharmacology)
• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (etiology)
• Bradykinin (pharmacology)
• Bradykinin Receptor Antagonists
• Endothelin Receptor Antagonists
• Endothelins (antagonists & inhibitors, pharmacology)
• Female
• Heart (physiopathology)
• L-Lactate Dehydrogenase (metabolism)
• Male
• Myocardial Ischemia (physiopathology)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (complications)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Rats
• Rats, Sprague-Dawley