Cardiovascular Study on the Effects of Combination of Direct Renin Inhibitor, Aliskiren, with Inhibitors of the Renin- Angiotensin- Aldosterone System in Diabetic Hypertensive Albino Rats

Abstract

Background & aim: Hypertension and diabetes mellitus (DM) are considered to be important risk factors for cardiovascular morbidity and mortality. Efficient antihypertensive therapy in diabetic patients should not only reduce the increased blood pressure (BP) but also reduce the diabetes-induced cardiovascular changes together with satisfactory control of hyperglycemia. The present study aimed to investigate the possible beneficial effects of combination of aliskiren with either perindopril or losartan in a model of hypertension and diabetes induced by deoxycorticosterone acetate and streptozotocin (DOCA-STZ) respectively in albino rats on selected cardiac indices measured by PowerLab AD instrument (left ventricular end diastolic pressure [LVEDP], LV dP/dtmax and mean aortic BP [ABP]), ECG intervals, blood glucose, renal functions & thiobarbituric acid reactive substances (TBARS) as a marker of lipid peroxidation in both heart and kideny homogenates, together with identification of histopathological changes in them. Methods: Albino rats were randomly divided into five groups (n/group=6): The first group: control group; received standard rat chow and tap water ad libitum for 5 weeks, the second group: DOCA-STZ untreated group; received DOCA doses twice weekly followed by single dose of STZ in the 2nd week with 1% NaCl added to the drinking water, the third group: DOCA-STZ group treated with aliskiren (20 mg/kg/day intraperitoneal for 3 weeks), the fourth group: DOCA-STZ group treated with a combination of aliskiren (20mg/kg/day) and perindopril (1mg/kg/day) intraperitoneal for 3 weeks and the fifth group: DOCA-STZ group treated with a combination of aliskiren (20mg/kg/day) and losartan (3mg/kg/day) intraperitoneal for 3 weeks. The duration of the whole study lasted for 5 weeks. Treatment was started after establishment of the model (at end of 2nd week) and lasted till the end of the study. Results: The present work showed that chronic treatment of hypertensive diabetic rats with aliskiren alone or in combination with either perindopril or losartan produced significant increase in LVEDP and LV dP/dt max and significant decrease in invasive mean ABP without significant difference between the treated groups. Regarding the effect on ECG, an apparent improvement compared to DOCA-STZ untreated group was seen in the treated groupswhich was more with aliskiren combination with losartan than with perindopril. Also, the present work showed that chronic treatment with aliskiren alone or in combination with either perindopril or losartan produced no significant difference in blood glucose level in these rats. The combination showed higher serum potassium and creatinine levels than aliskiren monotherapy but there was non significant difference in TBARS level in heart and kidney homogenates in the hypertensive diabetic albino rats. As regard the histopathological changes in the heart and kiney of these hypertensive diabetic rats, chronic treatment with aliskiren alone or in combination with losartan showed reduction of interstitial fibrosis compared to aliskiren combination with perindopril. Conclusion: Although the idea of adding aliskiren to angiotensin converting enzyme inhibitors and angiotensin receptor blockers theoretically achieve tighter renin-angiotensin-aldosterone system inhibition, this combination therapy in hypertensive diabetic model in rats did not add any significant additional benefit regarding improvement of either or both selected cardiac and renal functions. Furthermore; combination therapy failed to achieve normalization of mean BP compared to aliskiren monotherapy, probably due to deterioration of renal functions. Key words: aliskiren, perindopril,losartan, DOCA, STZ, hypertensive diabetic rats, LVEDP, LV dP/dtmax, ABP, ECG, potassium, creatinine, TBARS, heart histopathology, kidney histopathology.