Enhanced reduction of myocardial infarct size by combined ACE inhibition and AT1-receptor antagonism

1 The effects of the aniotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. 2 Both ACEI and AT(1)X reduce myocardial IS by a bradykinin-mediated process. It is unclear, however, whether the combination of ACEI and AT(1)A produces a more pronounced IS reduction than each of these drugs alone. 3 Forty-six enflurane-anaesthetized pigs underwent 90 min low-flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC-staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9+/-2 (s.e.mean) InmHg), AT(1)A (by 11+/-? mmHg) or their combination (by 18 +/- 3 mmHg, P < 0.05 vs ACEI and AT(1)A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n = 10), IS averaged 20.0 +/- 3.3% of the area at risk. IS was reduced to 9.8 +/- 2.6% with ramiprilat (n = 10) and 10.6+/-3.1% with candesartan (n = 10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7+/-2.1%. Blockade of the bradykinin-B-2-receptor with icatibant prior to ACEI and AT(1)A completely abolished the reduction of IS (n=6, 22.8+/-6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT(1)A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. 4 The combination of ACEI and AT(1)A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.