Protective effects of delapril combined with indapamide or hydrochlorothiazide in spontaneously hypertensive stroke-prone rats: A comparative dose-response analysis

In previous articles, we have shown that the combination of the angiotensin -converting enzyme (ACE) inhibitor delapril (12 mg/kg/day) and the diuretic indapamide (1 mg/kg/day) was able to prolong the life span significantly i n salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Because this finding was partly dependent on the antagonism of salt-loading effect s by pharmacologic induction of diuresis, which prevented any increase in b lood pressure values, we decided to evaluate whether lower doses of the com bination could be equally protective without changing the progression of hy pertension. Thus, we studied several treatments with progressively lower do ses of delapril (6, 3, or 1.5 mg/kg/day) combined with indapamide (0.5, 0.2 5, or 0.125 mg/kg/day) or hydrochlorothiazide (2.5, 1.25, or 0.625 mg/kg/da y) in salt-loaded SHRsp. Salt-loaded untreated animals were considered to b e the control group. In agreement with previous experiments, control rats r eached 50% mortality similar to 7 weeks after the beginning of salt loading . The combination of delapril and hydrochlorothiazide at the two lowest dos es was nor able to delay animal death significantly, whereas treatment with april and indapamide at the lowest dose was effective (50% survival rate, 15 weeks). The groups treated with the highest dose of delapril and hydroch lorothiazide or with the intermediate or highest dose of delapril and indap amide did not reach 50% mortality by the end of the experiment, at 44 weeks of treatment (i.e., when animals reached age 1 year). Only the highest del april and indapamide doses were able to increase diuresis, but for a relati vely short period. None of the treatments was able to lower or control bloo d pressure levels adequately. Therefore, blood pressure levels by themselve s were not predictive of rat mortality. In contrast, the maximal value of p roteinuria in the weeks preceding death was inversely correlated with the s urvival time. In conclusion, this study shows that low doses of an ACE inhi bitor in combination with a diuretic can be effectively protective in a mod el of severe hypertension, independent of any change in blood pressure leve ls.