Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor.

Abstract

SUMMARY The effects of angiotensin-converting enzyme inhibitor (CEI) SQ14225 on infarct size and regional myocardial blood flow were studied in 21 anesthetized dogs subjected to 6 hours of coronary occlusion. An area of myocardium at risk of necrosis was determined in vivo after 15 minutes of coronary occlusion but before CEI treatment (AR1) using an autoradiographic technique and after treatment after 6 hours of coronary occlusion (AR2) using a fluorescent dye technique. An MYOCARDIAL ISCHEMIA and, ultimately, infarction result from an imbalance between oxygen supply and oxygen demand. Coronary occlusion may induce hypotension, which results in baroreceptor activation and then systemic reflex vasoconstriction. -3 Systemic vasoconstriction may worsen the imbalance between myocardial oxygen supply and demand. Renal nerve activity,' a determinant of renin release,5 may be increased as well. Moreover, hypotension may activate intrarenal vascular pressoreceptors and may thus increase renin release directly.5 Because angiotensin II is a potent systemic and coronary vasoconstrictor, activation of the renin-angiotensin system may increase myocardial oxygen demand and decrease myocardial oxygen supply. Because interference with angiotensin II-production might exert a beneficial effect in myocardial ischemia and myocardial infarction, we studied the effects of the angiotensin-converting enzyme inhibitor (CEI) captopril (SQ14225) on infarct size after experimental coronary occlusion. To elucidate the mechanism of the salutary action of the drug, we also determined the effect of CEI on regional myocardial blood flow (RMBF) and measured plasma renin activity (PRA). Methods Twenty-one mongrel dogs of either sex weighing 16-28 kg that had been maintained on normal laboratory chow and had free access to water were anesthetized with i.v. thiamylal sodium (10 mg/kg), intubated and ventilated with room air using a Harvard respirator pump. Anesthesia was maintained by additional thiamylal sodium when needed. Lead aVF of the ECG was monitored. Saline was infused at a rate of 2 ml/min throughout the experiment to minimize hypovolemia and renin release. The chest was opened in the fifth left intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery was freed up approximately 2 cm from its origin just distal to the first major diagonal branch. Polyethylene catheters were placed in the femoral artery and vein and in the left atrial appendage. Arterial and left atrial pressures were measured by Statham P23Db pressure transducers.Infarct size after coronary occlusion depends on both the quantity of myocardium perfused by the occluded coronary vessel and the quantity of collateral flow to the jeopardized tissue.7'9 The variations in infarct size after coronary occlusion can be limited when these factors are taken into account by determining the area of myocardium at risk of developing necrosis and expressing infarct size as a percentage of the area at risk. In the present study, ...

Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs

“…In this respect, our results are in agreement with those of other studies performed with ACEIs (Liang et al, 1982;Daniell et al, 1984;De Lorgeril et al, 1992). In contrast, other investigators have reported an increase in regional myocardial blood flows and a limitation of infarct size with captopril in dogs (Ertl et al, 1982). However, several experiments suggest that the anti-ischaemic effect of the sulphydryl-containing ACEI captopril could be due to non specific effects of this drug, such as an inhibition of oxygen free radical-dependent reperfusion injury (Westlin & Mullane, 1988;Chopra et al, 1992) and/or an interference with arachidonic acid metabolism (Van Gilst et al, 1987).…”

“…It has been shown that blockade of the renin-angiotensin system by captopril (Ertl et al, 1982), enalapril (Lefer & Peck, 1984;Hock et al, 1985), and ramipril (Martorana et al, 1990) produces a beneficial effect in myocardial ischaemia. However, this cardioprotective effect of angiotensin Iconverting enzyme inhibitors (ACEIs) is not universally recognized, as Liang et al (1982) and Daniell et al (1984) have failed to demonstrate any myocardial protection with ACEIs.…”

Captopril in acute myocardial infarction: Beneficial effects on infarct size and arrhythmias

“…For C K and CK-MB determinations, blood samples were taken hourly for the first 6 h, and thereafter every 6 h for 48 h and beyond (assay: Merck, Darmstadt). Three patients in the placebo group required cardioversion for ventricular fibrillation; in two patients, this procedure was required more than once, and in these only CK-MB was taken into account.…”

Corcoran Lecture. Angiotensin-converting enzyme inhibition and the heart.

“…37 Some experimental studies reported that ACE inhibition in the immediate post-MI period could reduce both infarct size 38 and myocardial damage. 39 However, our own experiments failed to demonstrate a reduction of infarct size, 40 and a subsequent large clinical trial indicated that ACE inhibition given intravenously immediately after MI was not beneficial.…”