The net contribution of ET_A and ET_B receptors in blood pressure regulation in humans and experimental animals including the conscious mouse remains undefined. Thus, we assessed the role of ET_A and ET_B receptors in the control of basal blood pressure and also the role of ET_A receptors in maintaining the hypertensive effects of systemic ET_B blockade in telemetry-instrumented mice. Mean arterial pressure (MAP) and heart rate were recorded continuously from the carotid artery and daily (24-hr) values determined. At baseline, MAP ranged from 99 ± 1 to 101 ± 1 mmHg and heart rate ranged between 547 ± 15 and 567 ± 19 beats/min (n=6). Daily oral administration of the ET_B selective antagonist, A-192621 (10 mg/kg; BID), increased MAP to 108 ± 1 and 112 ± 2 mmHg on days 1 and 5, respectively. Subsequent co-administration of the ET_A selective antagonist, atrasentan (5 mg/kg BID), in conjunction with A-192621 (10 mg/kg; BID) decreased MAP to baseline values on day 6 (99 ± 2 mmHg) and to below baseline on day 8 (89 ± 3 mmHg). In a separate group of mice (n=6) in which the treatment was reversed systemic blockade of ET_B receptors produced no hypertension in animals pretreated with atrasentan underscoring the importance of ET_A receptors to maintain the hypertension produced by ET_B blockade. In a third group of mice (n=10), ET_A blockade alone (atrasentan; 5 mg/kg BID) produced an immediate and sustained decrease in MAP to values below baseline (baseline values = 101 ± 2 to 103 ± 2 mmHg; atrasentan decreased pressure to 95 ± 2 mmHg). Thus, these data suggest that ET_A and ET_B receptors play a physiologically relevant role in the regulation of basal blood pressure in normal, conscious mice. Furthermore, systemic ET_B receptor blockade produces sustained hypertension in conscious telemetry instrumented mice that is absent in mice pre-treated with an ET_A antagonist suggesting that ET_A receptors maintain the hypertension produced by ET_B blockade.