Enhanced reduction of myocardial infarct size by combined ACE inhibition and AT(1)-receptor antagonism

Abstract

The effects of the angiotensin-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. Both ACEI and AT(1)A 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. 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) mmHg), AT(1)A (by 11+/-2 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. 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.

Figure 1

Area at risk (AAR, left bars) was comparable between groups. Infarct size was reduced with ramiprilat, candesartan and both drugs combined. The infarct size reduction by combined drugs tended to be greater than that by either drug alone. Infarct size reduction by combined drugs was abolished by the bradykinin-B₂-receptor antagonist icatibant.

Figure 2

Relationships between subendocardial blood flow at 5 min ischaemia and infarct size. Subendocardial blood flow correlated inversely to infarct size in all groups of pigs. Infarct size for any given subendocardial blood flow was significantly reduced in pigs receiving ramiprilat (y= −212.6 × +20.7, n=10, r=−0.79) and candesartan (y= −276.9 × +24.5, n=10, r=−0.79) compared to placebo (y=−392.4 × +40.0, n=10, r=−0.94, p<0.05). The relationship between subendocardial blood flow and infarct size with combined drugs (y= −137.4 × +12.8, n=10, r=−0.71) was further shifted downwards and different from the relationships of all other groups (P⩽0.05).

Figure 3

Relationships between subendocardial blood flow at 5 min ischaemia and infarct size. The relationships for placebo and combined ramiprilat and candesartan in the presence of icatibant (y= −422.2 × +44.9, n=6, r=−0.95) were superimposable.