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

Abstract

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. 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. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), 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; P<0. 05). 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; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), 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. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin. British Journal of Pharmacology (2000) 129, 671 - 680

Figure 1

Experimental protocol for the studies involving Z13752A, and its modification by icatibant, an antagonist of bradykinin at B2 receptors. The duration of the Z13752A infusion was 1 h, the occlusion time was 25 min and icatibant was given 10 min prior to occlusion.

Figure 2

(a) Plasma ACE activity in anaesthetized dogs given intravenous infusion of vehicle (saline+NaOH 1N; n=6), Z13752A in doses of 0.3 μmol kg⁻¹ ml⁻¹ (128 μg kg⁻¹ ml⁻¹; n=6) and 1.0 μmol kg⁻¹ ml⁻¹ (426 μg kg⁻¹ ml⁻¹; n=6) and of captopril in a dose of 0.3 μmol kg⁻¹ ml⁻¹ (65 μg kg⁻¹ ml⁻¹; n=6) over a period of 3 h. Values are means±s.e.mean; ^*P<0.05 compared to the vehicle controls. (b) Ex vivo determination of tissue ACE and NEP activities, measured in the lung and in the kidney, respectively, following intravenous infusion of vehicle (saline+NaOH 1N; n=8), Z13752A in doses of 0.3 μmol kg⁻¹ ml⁻¹ (128 μg kg⁻¹ ml⁻¹; n=6) and 1.0 μmol kg⁻¹ ml⁻¹ (426 μg kg⁻¹ ml⁻¹; n=8) and of captopril in a dose of 0.3 μmol kg⁻¹ ml⁻¹ (65 μg kg⁻¹ ml⁻¹; n=6) over a period of 3 h. Values are means±s.e.mean; ^*P<0.05 compared to the vehicle controls.

Figure 3

Changes in diastolic coronary blood flow and resistance induced at the end of a 1 h infusion of Z13752A in a dose of 128 μg kg⁻¹ min⁻¹. There is an increase in blood flow in both the circumflex (LCX) and anterior descending (LAD) branches of the left coronary artery and a decrease in coronary vascular resistance. Values are means±s.e.mean; ^*P<0.05 compared to the identical values before giving Z13752A.

Figure 4

Changes in blood pressure induced by bolus injections of bradykinin in control, vehicle treated dogs (upper panels) and in dogs before and after the administration of Z13752A (lower panels). Values are means±s.e.mean; ^*P<0.05 compared to the values before giving Z13752A. #P<0.05 compared to the values of the vehicle-treated controls.

Figure 5

Changes in blood pressure induced by bolus injections of angiotensin I and angiotensin II in vehicle-treated control dogs (upper panels) and in dogs before and after the administration of Z13752A (lower panels). Values are means±s.e.mean; ^*P<0.05 compared to the values before giving Z13752A. #P<0.05 compared to the values of the vehicle-treated controls.

Figure 6

The distribution of ventricular arrhythmias in control dogs, and in dogs infused with Z13752A, with and without icatibant, during a 25 min coronary artery occlusion followed, at the end of this period, by reperfusion. The ACE/NEP inhibitor markedly reduced the severity of these arrhythmias and 6/9 dogs survived the combined ischaemia-reperfusion insult. This protective effect was reversed by icatibant suggesting a role, in the protection, for bradykinin.

Figure 7

A summary of the effects of Z13752A, with or without icatibant, and of icatibant alone in comparison with control (saline infused) dogs, on ventricular arrhythmias resulting from coronary artery occlusion and subsequent reperfusion. VPBs=ventricular premature beats; VT=ventricular tachycardia; VF=ventricular fibrillation (during occlusion and reperfusion) and SUR=survival. The marked antiarrhythmic effect of Z13752A is abolished by icatibant. Values are means±s.e.mean; ^*P<0.05 c.p. controls.

Figure 8

(a) Changes in epicardial ST segment during a 25 min occlusion of the left anterior descending coronary artery in anaesthetized dogs given saline, Z13752A, icatibant and Z13752A in the presence of icatibant. The administration of the ACE/NEP inhibitor leads to a reduction in the severity of the ischaemia, an effect reversed by icatibant. Values are means±s.e.mean; ^*P<0.05 c.p. control group. (b) Changes in the degree of inhomogeneity of electrical activation during a 25 min occlusion of the left anterior descending coronary artery in control dogs, in dogs given Z13752A, in dogs given icatibant and in dogs given Z13752A in the presence of icatibant. The reduction in this index of the severity of ischaemia is reduced by Z13752A and, again, this is reversed by icatibant. Values are means±s.e.mean; ^*P<0.05 c.p. control group.