Chronic low-dose treatment with perindopril improves cardiac function in stroke-prone spontaneously hypertensive rats by potentiation of endogenous bradykinin

Abstract

We investigated the effect of chronic angiotensinconverting enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2receptor antagonist, icatibant (500 μg/kg/day s.c), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic highdose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, lowdose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dP/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacyclin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin. We investigated the effect of chronic angiotensinconverting enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2receptor antagonist, icatibant (500 μg/kg/day s.c), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic highdose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, lowdose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dP/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacyclin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.