Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade.
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.
Fryer
Ryan M
RM
Department of Integrative Pharmacology, R46R, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6119, USA. ryan.fryer@abbott.com
Rakestraw
Pamela A
PA
Banfor
Patricia N
PN
Cox
Bryan F
BF
Opgenorth
Terry J
TJ
Reinhart
Glenn A
GA
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065131:Endothelin B Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000187:drug effects*; D013686:Telemetry
C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan