Hypertension induced by blockade of ET(B) receptors in conscious nonhuman primates: role of ET(A) receptors.
The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.
Reinhart
Glenn A
GA
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. glenn.reinhart@abbott.com
Preusser
Lee C
LC
Burke
Sandra E
SE
Wessale
Jerry L
JL
Wegner
Craig D
CD
Opgenorth
Terry J
TJ
Cox
Bryan F
BF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003243:Consciousness; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D013686:Telemetry
C120508:A 192621; D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000077868:Atrasentan