Improvement of endothelial function with the fixed low-dose perindopril-indapamide combination

Fixed-dose combinations of angiotensin-converting enzyme (ACE) inhibitors w ith diuretics have been shown to be particularly useful in terms of clinica l efficacy, compliance and side-effects. However, although the vascular end othelium appears to be a major target of various cardiovascular diseases an d especially of hypertension, only a few reports link the efficacy of such combined treatment with low doses of both compounds in terms of endothelial function. In spontaneously hypertensive rats, the antihypertensive effects of chronic treatment with a fixed low-dose combination of the ACE inhibitor perindopr il and the diuretic indapamide have been compared with that of each drug ad ministered alone. The effects of this combined treatment on endothelial fun ction and on target organs of hypertension were assessed in parallel. After chronic treatment with placebo or increasing doses of the combination (0.3 , 1 and 3 mg. kg(-1). day (-1); ratio of indapamide/perindopril, 0.32), sys tolic blood pressure decreased in a dose-dependent way. Moreover, the antih ypertensive effect of the combination (1 mg. kg(-1).day(-1)) was more marke d than that induced by each treatment administered alone. In aortic rings m ounted in organ chambers, the combination increased basal release of NO (as sessed as the contractile responses to serotonin in the absence or in the p resence of NG-nitro-L-arginine as the inhibitor of NO synthesis), and decre ased the release of endothelium-derived contracting factors (EDCF) (assesse d as the response to acetylcholine in the presence of NG-nitro-L-arginine). In Dahl salt-sensitive rats, a model of hypertension characterized by a low production of NO, the fixed perindopril-indapamide combination also decrea sed arterial pressure, increased the relaxations induced by acetylcholine a nd increased eNOS activity. It appears that this fixed low-dose combination has potent antihypertensive properties, and also exerts protective effects on endothelial function in different experimental models of hypertension. Experiments are currently un derway to determine whether such endothelial protective effects also occur in hypertensive patients.