EFFECTS OF LOCAL INHIBITION OF THE CARDIAC RENIN-ANGIOTENSIN SYSTEM WITH CV-11974 IN A CANINE ISCHAEMIA-REPERFUSION MODEL

SUMMARY 1. To determine whether total interruption of the local cardiac renin-angiotensin system by angiotensin II (AngII) receptor antagonist limits myocardial ischaemia, intracoronary (i.e.) or intravenous (i.v.) infusion of Angll receptor antagonists was compared in ischaemic dogs. 2. Dogs subjected to 90min coronary artery occlusion and 270 min reperfusion assigned to saline (n= 10) or i.e. low dose (LD, n= 10), i.v. low dose (n= 10) or i.v. high dose (HD, n= 10) of AngII AT1-receptor antagonist, CV-11974. The CV-11974 was infused from 15 min pre-occlusion for 180 min. Cardiac and regional function, area at risk and infarct size were measured. 3. Although i.e. CV-11974 did not cause systemic haemodynamic changes, it abolished reduction in coronary blood flow induced by i.e. AngII injection. Elevation in LV end-diastolic pressure during ischaemia was smaller in both i.e. and i.v.-HD CV-11974 dogs than in i.v.-LD and control dogs. Regional wall thickening was not different among the four groups. With comparable area at risk, i.e. CV-11974 reduced infarct size to the same extent as i.v.-HD CV-11974 (18 vs 21%), which was smaller than i.v.-LD CV or the controls (38 and 42%). 4. The results indicate that AngII receptor antagonist can reduce ischaemia-reperfusion injury in experimental ischaemia. These cardioprotective effects might be mediated through direct inhibition of local angiotensin action in the heart. Local cardiac AngII formation may play a crucial role in cardiac injury during ischaemia and reperfusion.