EFFECT OF LOW-DOSE TREATMENT WITH PERINDOPRIL ON CARDIAC-FUNCTION IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS - ROLE OF BRADYKININ

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac fun ction independent of their blood pressure (BP)-lowering actions. We in vestigated the effect of chronic subantihypertensive ACE inhibitor tre atment on functional and biochemical cardiac parameters in stroke-pron e spontaneously hypertensive rats (SHRSP). Animals were treated in ute ro and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) pote ntiation to the actions of the ACE inhibitor was assessed by cotreatme nt with the BK beta(2)-receptor antagonist Hoe 140 (500 mu g/kg/day su bcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myoca rdial prostacyclin and cyclic GMP concentrations. Chronic low-dose per indopril treatment had no effect on development of hypertension and le ft ventricular hypertrophy (LVH), but perindopril improved cardiac fun ction, as demonstrated by increased LV pressure (LVP) (19.4%) and LV d p/dt(max) (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactat e concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glyc ogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on c ardiac function and metabolism were abolished by concomitant chronic B K receptor blockade. Cardiac prostacyclin concentrations were threefol d elevated in perindopril-treated animals whereas cardiac cyclic GMP c oncentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can im prove cardiac function and metabolism by potentiating endogenous BK. T hese effects are independent of the antihypertensive and antihypertrop hic drug actions and may be mediated by BK-induced prostacyclin genera tion.