Role of bradykinin and eNOS in the anti-ischaemic effect of trandolapril

1 Angiotensin converting enzyme (ACE) inhibitors are under study in ischaem ic heart diseases, their mechanism of action being still unknown. 2 The anti-ischaemic effect of trandolapril and the possible involvement of a bradykinin-modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated. 3 Three doses of trandolapril, chronically administered in vivo, were studi ed in isolated perfused rat hearts subjected to global ischaemia followed b y reperfusion. 4 Trandolapril has an anti-ischaemic effect. The dose of 0.3 mg kg(-1) exer ted the best effect reducing diastolic pressure increase during ischaemia ( from 33.0 +/- 4.5 to 14.0 +/- 5.2 mmHg; P < 0.05 vs control) and reperfusio n (from 86.1 <plus/minus> 9.4 to 22.2 +/- 4.1 mmHg; P < 0.01 vs control), i mproving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion. 5 Trandolapril down-regulated the baseline developed pressure. 6 Trandolapril increased myocardial bradykinin content (from 31.8 <plus/min us> 6.1 to 54.8 +/- 7.5 fmol/gww; P < 0.05, at baseline) and eNOS expressio n and activity in aortic endothelium (both P < 0.01 vs control) and in card iac myocytes (from 11.3 +/- 1.5 to 17.0 +/- 2.0 mUOD mug protein(-1) and fr om 0.62 +/- 0.05 to 0.80 +/- 0.06 pmol mg prot(-1) min(-1); both P < 0.05 v s control). 7 HOE 140 (a bradykinin B-2 receptor antagonist) and NOS inhibitors counter acted the above-reported effects. 8 There was a negative correlation between myocyte's eNOS up-regulation and myocardial contraction down-regulation, 9 Our findings suggest that the down-regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin-mediated increase in N O production, plays a crucial role in the anti-ischaemic effect of trandola pril by reducing energy breakdown during ischaemia.