Attenuation of Reperfusion Arrhythmias by Selective Inhibition of Angiotensin-Converting Enzyme/Kininase II in the Ischemic Zone: Mediated by Endogenous Bradykinin?

Abstract

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.

Inhibition of Angiotensin-Converting Enzyme Reduces Susceptibility of Hypertrophied Rat Myocardium to Ventricular Fibrillation.

“…Fig 2 summarizes the overall incidences of reperfusion-induced VT and VF. Consistent with our previous study, 32 the incidence of reperfusion-induced VF in the non-hypertrophied hearts in the SH control group subjected to 7 min of regional ischemia was 33%. AC increased the VF incidence to 92% (p<0.05 vs SH).…”

“…32 Bradykinin B2 receptor antagonist HOE140 reversed that effect, indicating that antiarrhythmic effects are mediated through suppression of tissue ACE activity and a subsequent increase in endogenous bradykinin in ischemic myocardium. 32 It has been shown that bradykinin mediates the anti-hypertrophic effects of ramipril (at the same doses used in the present study) 33,40 and contributes to improvement of both metabolism and contractile function in hypertrophied myocardium. 41,42 That indicates that an increase in endogenous bradykinin may mediate the anti-arrhythmic effects of ramipril.…”

Impact of Myocardial Angiotensin-Converting Enzyme Activity on Coronary Vascular Resistance and Serum Brain Natriuretic Peptide Concentration in Coronary Bypass Surgery

“…7 The infusion flow rate of the cardioplegic solution was recorded with the flow meter of the cardiopulmonary bypass machine. The rate was usually fixed between 200 and 300 ml/min.…”

Effects of enalapril and losartan on circulating adhesion molecules and monocyte chemotactic protein-1

“…Angiotensin-converting enzyme inhibitors (ACE-Is) are well-established drugs for patients with hypertension, heart failure or diabetic microalbuminuria, with beneseveral animal models have shown that some of the cardioprotective effects of ACE-Is could be attributed to bradykinin [3]. Bradykinin stimulates NO production by endothelial cells, and may thereby help to ' correct ' endothelial dysfunction [4].…”