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

1, To determine whether total interruption of the local cardiac renin- angiotensin system by angiotensin II (AngII) receptor antagonist limit s myocardial ischaemia, intracoronary (i.c,) or intravenous (i,v,) inf usion of AngII receptor antagonists was compared in ischaemic dogs. 2, Dogs subjected to 90 min coronary artery occlusion and 270 min reperf usion assigned to saline (n = 10) or i,c. low dose (LD, n = 10), i.v, low dose (n = 10) or i,v, high dose (HD, n = 10) of AngII AT(1)-recept or antagonist, CV-11974, The CV-11974 was infused from 15 min pre-occl usion for 180 min, Cardiac and regional function, area at risk and inf arct size were measured. 3, Although i,c, CV-11974 did not cause syste mic haemodynamic changes, it abolished reduction in coronary blood flo w induced by i.c, AngII injection. Elevation in LV end-diastolic press ure during ischaemia was smaller in both i,c, and i,v,-HD CV-11974 dog s than in i,v,-LD and control dogs. Regional wall thickening was not d ifferent among the four groups. With comparable area at risk, i,c, 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 i schaemia-reperfusion injury in experimental ischaemia, These cardiopro tective effects might be mediated through direct inhibition of local a ngiotensin action in the heart, Local cardiac AngII formation may play a crucial role in cardiac injury during ischaemia and reperfusion.