Patients with hypercholesterolemia without vascular disease have an impaired endothelium-dependent (nitric oxide-mediated) vasodilation in coronary and peripheral vascular beds. This study was designed to establish whether hypercholesterolemia (and its reduction) affects also the microcirculation vasomotion during postischemic hyperemia in both calf and forearm. Thirteen male patients, aged 36.2+/-8.5 years, mean +/-SD, with heterozygous familial hypercholesterolemia and 10 male control subjects, aged 32.2+/-3.6 years free from vascular lesions were studied. Plasma lipids, hematologic parameters, and limb vasoreactivity were evaluated while the patients were treated only with diet and during therapy with simvastatin. Calf and forearm blood flows were determined by venous occlusion strain gauge plethysmography at rest, during reactive hyperemia, and after sublingual isosorbide dinitrate administration. Calf resting flow rate of the hypercholesterolemic patients during and without treatment was similar to that of the controls. Calf resting vascular resistance was greater in the untreated hypercholesterolemic subjects than in the normal controls, but during treatment this difference was abolished. Peak flow during reactive hyperemia and flow debt repayment were lower in the untreated hypercholesterolemic subjects as compared to the controls, but they were normalized following hypocholesterolemic therapy. No differences were observed in forearm blood flow measurements between hypercholesterolemic subjects (without and during therapy) and control subjects. The blood flow and vascular resistance after isosorbide dinitrate were modified in a similar manner in the hypercholesterolemic (without and during therapy) and control subjects at both calf and forearm. Hypercholesterolemia does not affect vasodilation in the forearm as determined by postocclusive reactive hyperemia, while in the calf hypercholesterolemia is associated with higher resting vascular resistance, lower peak flow during reactive hyperemia, and lower flow debt repayment. These abnormalities are corrected by the hypocholesterolemic treatment.