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EXPERIMENTAL STUDY

Angiotensin-converting enzyme inhibition enhances a subthreshold stimulus to elicit delayed preconditioning in pig myocardium

M. T. Jaberansari, MD^*, Gary F. Baxter, PhD, FIBiol, Cecile A. Muller, PhD, Sean E. Latouf, MD, E. Röth, MD, DSc^*, Lionel H. Opie, MD, DPhil, FACC and Derek M. Yellon, DSc, FACC

^* Department of Experimental Surgery, PTE, Pécs, Hungary
The Hatter Institute, UCL Medical School, London, United Kingdom
Cape Heart Centre, University of Cape Town, Cape Town, South Africa

Manuscript received October 10, 2000; revised manuscript received January 30, 2001, accepted February 15, 2001.

Reprint requests and correspondence: % Prof. Derek M. Yellon, Director of Institute and Head of Centre for Cardiology, The Hatter Institute for Cardiovascular Studies, Centre for Cardiology, UCL Hospitals and Medical School, Grafton Way, London WC1E 6DB, United Kingdom
hatter-institute{at}ucl.ac.uk

OBJECTIVES

We assessed the effect of angiotensin-converting enzyme (ACE) inhibition in combination with a subthreshold preconditioning (PC) stimulus to elicit delayed preconditioning against infarction in pig myocardium.

BACKGROUND

Bradykinin triggers early PC. Angiotensin-converting enzyme inhibitors increase local bradykinin levels via inhibition of kinin breakdown and have been shown in experimental studies to augment early protection afforded by PC. A role for bradykinin in eliciting delayed PC has not so far been identified.

METHODS

We used a two-day protocol. On day 1 (closed chest), pigs were either sham-operated (group 1) or preconditioned, using balloon catheter inflation of the left anterior descending (LAD) coronary artery, with either a full (4 x 5 min PC, group 2) or subthreshold PC stimulus (2 x 2 min PC, group 3). Additional groups were pre-treated with perindoprilat (0.06 mg/kg i.v.) before sham (group 4) or subthreshold PC (group 5). On day 2 (open chest), all pigs were subjected to 40 min occlusion of the LAD followed by 3 h of reperfusion. Infarct size was determined by tetrazolium staining.

RESULTS

Group 1 had a mean infarct size of 42.8 ± 3.2% of the risk zone. Preconditioning with 4 x 5 min reduced the infarct size to 19.5 ± 3.9% (p < 0.05). Groups 3 and 4 had infarct sizes not statistically different from group 1. However, combining perindoprilat with subthreshold PC resulted in a significant limitation of the infarction (18.4 ± 3.1% p < 0.05), comparable with group 2.

CONCLUSIONS

This is the first study to show that ACE inhibition can augment a mild ischemic stimulus to induce a protected state 24 h later.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ANOVA = analysis of variance   BP = blood pressure   i.v. = intravenously   LAD = left anterior descending coronary artery   LCA = left coronary artery   NO = nitric oxide   PC = ischemic preconditioning   PTCA = percutaneous transluminal coronary angioplasty   VF = ventricular fibrillation   VT = ventricular tachycardia

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