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Blood pressure regulation by ET_A and ET_B receptors in conscious, telemetry-instrumented mice and role of ET_A in hypertension produced by selective ET_B blockade

¹Integrative Pharmacology and ²Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Submitted 18 November 2005 ; accepted in final form 4 January 2006

The net contribution of endothelin type A (ET_A) and type B (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 h) 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 twice daily] increased MAP to 108 ± 1 and 112 ± 2 mmHg on days 1 and 5, respectively. Subsequent coadministration of the ET_A selective antagonist atrasentan (5 mg/kg twice daily) in conjunction with A-192621 (10 mg/kg twice daily) 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 twice daily) 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 pretreated with an ET_A antagonist, suggesting that ET_A receptors maintain the hypertension produced by ET_B blockade.

atrasentan; A-192621; endothelin; mouse; vasculature

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