CHRONIC LOW-DOSE TREATMENT WITH PERINDOPRIL IMPROVES CARDIAC-FUNCTIONIN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS BY POTENTIATION OF ENDOGENOUS BRADYKININ

We investigated the effect of chronic angiotensin-converting enzyme (A CE) inhibitor treatment on functional and biochemical cardiac paramete rs in stroke-prone spontaneously hypertensive rats (SHRsp). Animals we re treated prenatally and, subsequently, up to the age of 20 weeks wit h the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contri bution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B-2-recept or antagonist, icatibant (500 mu g/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosin e monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventr icular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac fu nction of isolated perfused hearts as demonstrated by an increasing le ft ventricular pressure and dP/dt(max) without change in heart rate. L ow-dose perindopril further reduced lactate concentrations and the enz ymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycog en, adenosine triphosphate, and creatine kinase in the myocardium. Con comitant chronic bradykinin receptor blockade abolished all ACE inhibi tor-induced effects on cardiac function and metabolism. Cardiac prosta cyclin concentrations were 3-fold elevated in perindopril-treated anim als when compared to vehicle-treated controls, while cardiac cyclic GM P concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism i ndependently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.