The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin

Abstract

1 The e ects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. 2 A 1 h infusion of Z13752A (128 mg kg 71 min 71 intravenously) decreased arterial blood pressure (by 11+3%; P50.05) and increased coronary blood¯ow (by 12+4%, P50.05). There were no other signi®cant haemodynamic changes. 3 Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. 4 When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular ®brillation (VF) occurred (compared to 7/16 in the controls; P50.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+0.1 c.p. 10.7+3.3; P50.05). 5 Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P50.05). 6 Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. 7 These protective e ects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg 71 , i.v.) a selective antagonist of bradykinin at B 2 receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. 8 We conclude that this ACE/NEP inhibitor is e ective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin.

Cardioprotective actions of peptide hormones in myocardial ischemia

“…Inhibition of kinin breakdown has been shown to be an effective method for inducing protection of the ischemic myocardium [102][103][104][105][106][107][108]. Administration of the ACE inhibitors enalapril or lisinopril, to rat intact hearts subjected to left coronary artery ligation (30 min) and reperfusion, produced a significant reduction in infarct size [109].…”

Role of ACE and NEP in bradykinin-induced relaxation and contraction response of isolated porcine basilar artery

“…It is important to compare the affinities of BK and a B 2 -receptor antagonist for B 2 -receptors in the absence or presence of ACE and NEP inhibitors for evaluating the role of ACE and NEP on BK degradation, because we have shown that captopril increases the affinity of BK to B 2 -receptor binding sites in bovine coronary arterial endothelial cells (Miyamoto et al 2000). Recently, several dual inhibitors of ACE and NEP have been developed for the treatment of hypertension, myocardial ischemia and coronary artery occlusion (Fournié-Zaluski et al 1994;Chatelain et al 1998;Rastegar et al 2000). However, some reports showed that a NEP inhibitor (phosphoramidon) did not further potentiate the maximal effect of ACE inhibitor (captopril) on BK-induced arteriolar dilation (Gao et al 1994) and BK degradation (Ishida et al 1989).…”

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“…9) are some more novel ACE/NEP inhibitors. The latter compound has also shown efficacy against ventricular fibrillation and tachycardia in a canine model of coronary artery occlusion which is attributed to the protective effects of increased bradykinin levels 26 . The concept of triple vasopeptidase inhibition has recently gained interest.…”