icatibant and Coronary-Disease

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

Topics: Adrenergic beta-Antagonists; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Blood Pressure; Bradykinin; Coronary Circulation; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Female; Kidney; Lung; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Neprilysin; Peptidyl-Dipeptidase A; Phenylalanine

In dogs, rapid cardiac pacing, by way of a pacing electrode in the right ventricle, protects against ventricular arrhythmias when a coronary artery is occluded immediately after cessation of the pacing period. This represents a form of ischaemic preconditioning. The role of bradykinin in mediating the protective effects of rapid cardiac pacing in this model was investigated using a selective antagonist of bradykinin at B2 receptors (icatibant; HOE 140). In the presence of icatibant cardiac pacing (220 beats min(-1)) resulted in more severe ischaemia (as assessed by ST-segment elevation from the pacing electrode at the end of the stimulus) and to a higher incidence of ventricular arrhythmias during the pacing protocol. When the coronary artery was occluded under such conditions the antiarrhythmic protection afforded by cardiac pacing was not seen although other indices of reduced ischaemia severity (epicardial ST-segment mapping; changes in the degree of inhomogeneity of electrical activation within the ischaemic area) were not affected by icatibant treatment. These results suggest that bradykinin is an important trigger mediator involved in the protective effects of cardiac pacing. Whether this is due to the generation of endothelium-derived protective substances (such as nitric oxide and prostacyclin) or whether it results from a direct effect on B2 receptors in cardiac myocytes is unclear.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Animals; Arrhythmias, Cardiac; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cardiac Pacing, Artificial; Coronary Disease; Disease Models, Animal; Dogs; Female; Heart Rate; Ischemic Preconditioning; Male; Myocardial Ischemia; Receptor, Bradykinin B2; Ventricular Function, Left