We tested the effects of indapamide (IND), an antihypertensive drug, on the contractile responsiveness of femoral and mesenteric arteries isolated from rabbits fed with a 1% cholesterol diet for 16 weeks. IND (0.1, 0.3, 1 mg/kg/day) was given to the experimental groups of rabbits, whereas control groups received either a standard or a cholesterol-enriched diet. Contractions caused by submaximal doses of norepinephrine (NE) or high-K were significantly decreased in the femoral artery of untreated hypercholesterolemic rabbits. The responses to NE(10(-6) M) or to KCI (80 mM) expressed as a percentage of the control group (standard diet) contractions were 77.0 +/- 3.3% and 55.0 +/- 4.2%, respectively. Vascular reactivity was preserved in the rabbits fed the atherogenic diet supplemented with IND in a concentration-dependent manner. In addition, in the experimental groups dose-response curves to NE (10(-8) to 10(-4) M) and to KCI (20-120 mM) were shifted upward and to the left with respect to the control hypercholesterolemic group. In the mesenteric artery (fifth branch) NE- and K-induced contractions were not significantly altered by hypercholesterolemia. We conclude that IND treatment may prevent femoral arteries from a loss of reactivity probably by reducing the severity of atherosclerosis.