This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brunner, F. Articles by Kukovetz, W. R. Search for Related Content PubMed PubMed Citation Articles by Brunner, F. Articles by Kukovetz, W. R.

(Circulation. 1996;94:1752-1761.)
© 1996 American Heart Association, Inc.

Articles

Postischemic Antiarrhythmic Effects of Angiotensin-Converting Enzyme Inhibitors

Role of Suppression of Endogenous Endothelin Secretion

Friedrich Brunner, PhD; Walter R. Kukovetz, MD

the Institut fur Pharmakologie und Toxikologie, Karl-Franzens-Universitat Graz, A-8010 Graz, Austria.

Correspondence to Friedrich Brunner, PhD, Institut fur Pharmakologie und Toxikologie, Karl-Franzens-Universitat Graz, Universitatsplatz 2, A-8010 Graz, Austria. E-mail friedrich.brunner@kfunigraz.ac.at.

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 µmol/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 µmol/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.

Key Words: endothelin • ischemia • reperfusion • angiotensin • arrhythmia • hemodynamics

This article has been cited by other articles:

				M. Kakoki, R. W. McGarrah, H.-S. Kim, and O. Smithies Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury PNAS, May 1, 2007; 104(18): 7576 - 7581. [Abstract] [Full Text] [PDF]

				N. H.S. Kim and L. J. Rubin Endothelin in Health and Disease: Endothelin Receptor Antagonists in the Management of Pulmonary Artery Hypertension Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 9 - 19. [Abstract] [PDF]

				M. E. Khalil, A. W. Basher, E. J. Brown Jr, and I. A. Alhaddad A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1757 - 1764. [Abstract] [Full Text] [PDF]

				F. Duru, M. Barton, T. F. Luscher, and R. Candinas Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs? Cardiovasc Res, February 1, 2001; 49(2): 272 - 280. [Abstract] [Full Text] [PDF]

				B.-q. Zhu, Y.-p. Sun, R. E. Sievers, A. E. M. Browne, S. Pulukurthy, K. Sudhir, R. J. Lee, T. M. Chou, K. Chatterjee, and W. W. Parmley Comparative effects of pretreatment with captopril and losartan on cardiovascular protection in a rat model of ischemia-reperfusion J. Am. Coll. Cardiol., March 1, 2000; 35(3): 787 - 795. [Abstract] [Full Text] [PDF]

				K. Alexiou, T. Dschietzig, O. Simsch, M. Laule, J. Hundertmark, G. Baumann, and K. Stangl Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin: Aggravation of this phenomenon in heritable hyperlipidemia J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1773 - 1778. [Abstract] [Full Text] [PDF]

				F. Brunner and L. H. Opie Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury Circulation, February 3, 1998; 97(4): 391 - 398. [Abstract] [Full Text] [PDF]

				G. A. Rongen, S. C. Brooks, S.-i. Ando, H. R. Dajani, B. L. Abramson, and J. S. Floras Neural and Hypotensive Effects of Angiotensin II Receptor Blockade Hypertension, January 1, 1998; 31(1): 378 - 383. [Abstract] [Full Text] [PDF]

				C. Kupatt, H. Habazettl, S. Zahler, C. Weber, B. F Becker, K. Messmer, and E. Gerlach ACE-inhibition prevents postischemic coronary leukocyte adhesion and leukocyte-dependent reperfusion injury Cardiovasc Res, December 1, 1997; 36(3): 386 - 395. [Abstract] [Full Text] [PDF]