Endothelin and ET(A) receptors in long-term arterial pressure homeostasis in conscious nonhuman primates.
This study was designed to quantify the long-term contribution of endogenous endothelin-1 (ET-1) and ET(A) receptors to the regulation of arterial pressure under normal conditions in nonhuman primates. Therefore, mean arterial pressure (MAP) and heart rate were measured 24 h/day with the use of telemetry techniques in conscious cynomolgus monkeys under control conditions, during administration of an ET(A) selective receptor antagonist (ABT-627; 5 mg/kg, 2 times a day by mouth, 4 days), and a 6-day posttreatment period. Systemic ET(A) blockade reduced MAP (24 h) from 89 +/- 3 to 82 +/- 2 and 79 +/- 2 mmHg on days 1 and 4, respectively. Subsequently, MAP remained suppressed for 3 days posttreatment. Heart rate increased from 111 +/- 5 to 122 +/- 4 and 128 +/- 6 beats/min on days 1 and 4 of ABT-627, respectively, and remained above control for 3 days posttreatment. Plasma ET-1 concentration increased from 1.0 +/- 0.3 to 1.9 +/- 0.4 pg/ml in response to ABT-627 (day 4) but decreased to control values 4 days posttreatment. These data demonstrate a physiologically important role for endogenous ET-1 and ET(A) receptors in the long-term regulation of arterial pressure and plasma ET-1 levels in the conscious nonhuman primate.
Reinhart
G A
GA
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. glenn.reinhart@abbott.com
Preusser
L C
LC
Opgenorth
T J
TJ
Wegner
C D
CD
Cox
B F
BF
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D006339:Heart Rate; D006400:Hematocrit; D006706:Homeostasis; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D011188:Potassium / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D012964:Sodium / Q000097:blood
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D012964:Sodium; D011188:Potassium; D000077868:Atrasentan