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

Fixed-dose combinations of angiotensin-converting enzyme (ACE) inhibitors with diuretics have been shown to be particularly useful in terms of clinical efficacy, compliance and side-effects. However, although the vascular endothelium appears to be a major target of various cardiovascular diseases and 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 perindopril and the diuretic indapamide have been compared with that of each drug administered alone. The effects of this combined treatment on endothelial function 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), systolic blood pressure decreased in a dose-dependent way. Moreover, the antihypertensive effect of the combination (1 mg. kg(-1).day(-1)) was more marked than that induced by each treatment administered alone. In aortic rings mounted in organ chambers, the combination increased basal release of NO (assessed as the contractile responses to serotonin in the absence or in the presence of NG-nitro-L-arginine as the inhibitor of NO synthesis), and decreased the release of endothelium-derived contracting factors (EDCF) (assessed 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 decreased arterial pressure, increased the relaxations induced by acetylcholine and 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 underway to determine whether such endothelial protective effects also occur in hypertensive patients.