Dysfunction of pulmonary endothelial cells plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH). We were interested in studying patients with idiopathic PAH, their relatives, and patients with PAH secondary to systemic sclerosis to see whether there was evidence of systemic endothelial cell function. We chose to study both nitric oxide (NO)-dependent and NO-independent mechanisms by studying brachial artery hyperemia flow-mediated vasodilation following occlusion (NO-dependent) and response to sublingual glyceryl trinitrate (GTN) [NO-independent]. We studied 10 control subjects, 10 patients with PAH due to idiopathic pulmonary hypertension, 10 of their relatives, and 10 patients with PAH due to systemic sclerosis. Brachial artery dilation was measured using a 12-MHz ultrasound probe. Brachial arterial dilation was measured 60 s after the release of the occluding cuff and 3 min after sublingual GTN administration. There were significant reductions in brachial artery dilation seen in patients with idiopathic PAH and in those with systemic sclerosis compared to control subjects (2.7% vs 6.3%, respectively [p < 0.05]; and 0.7% vs 6.3%, respectively [p < 0.05]). Most interesting was the observation that there was a trend toward a reduced response in family members of the idiopathic PAH patients (2.7% vs 6.3%, respectively). Three family members showed a particularly reduced response.