Endothelin contributes to abnormalities in peripheral blood vessel function of subjects with obesity, with or without concurrent type 2 diabetes mellitus, but it is unknown if endothelin contributes specifically to obesity and diabetes-associated changes in blood pressure. We evaluated the effect of systemic endothelin antagonism on peripheral and central hemodynamics and peripheral vascular tone in lean, obese, and type 2 diabetic subjects without overt hypertension by cuff plethysmography. We measured the effects of acute systemic infusions of BQ123 (an antagonist of type A endothelin receptors) in seven lean (body mass index [BMI] 22.7 +/- 3.2 kg/m(2)), seven obese (BMI 35.8 +/- 4.6), and six diabetic subjects (BMI 38.2 +/- 5.0, glycosylated hemoglobin 8.1 +/- 2.2%). BQ123 was infused via antecubital vein sequentially at infusion rates from 0.1 to 1.0 mumol/min. Diastolic blood pressure was significantly lower than baseline across this dose range, but without a clear dose dependence and without differences in the dose response across groups. Obese and diabetic subjects exhibited progressive dilation of peripheral blood vessels (P </= .01), with 0.03 and 1.0 mumol/min BQ123 (P = .03 comparing integrated response across groups). No significant changes were observed in systolic blood pressure, cardiac index, or stroke index. These observations confirm the relevance of endothelin in the abnormal regulation of peripheral vascular tone in obesity and diabetes, but they argue against a specific effect of endothelin in diabetes- and obesity-associated blood pressure elevations.