| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-6119
The role of endothelin-B (ETB) 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 ETB blockade and the role of ETA 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 ETB-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ETA antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ETB 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 ETB blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ETA receptors. These data suggest an importance clearance function for ETB receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ETA activation.
endothelium-derived factors; blood pressure; endothelin receptor blockade
This article has been cited by other articles:
|
|
 |
|
  G. Fink, M. Li, Y. Lau, J. Osborn, and S. Watts Chronic Activation of Endothelin B Receptors: New Model of Experimental Hypertension Hypertension, September 1, 2007; 50(3): 512 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Battistini, N. Berthiaume, N. F. Kelland, D. J. Webb, and D. E. Kohan Profile of Past and Current Clinical Trials Involving Endothelin Receptor Antagonists: The Novel "-Sentan" Class of Drug. Experimental Biology and Medicine, June 1, 2006; 231(6): 653 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Tsai, M. Ohkita, and C. E. Gariepy Chronic high-sodium diet increases aortic wall endothelin-1 expression in a blood pressure-independent fashion in rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 813 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Sullivan, J. S. Pollock, and D. M. Pollock Superoxide-dependent hypertension in male and female endothelin B receptor-deficient rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 818 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Fryer, P. A. Rakestraw, P. N. Banfor, B. F. Cox, T. J. Opgenorth, and G. A. Reinhart Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2554 - H2559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. E. Lau, J. J. Galligan, D. L. Kreulen, and G. D. Fink Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R90 - R95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Honore, M.-H. Fecteau, I. Brochu, J. Labonte, G. Bkaily, and P. D'Orleans-Juste Concomitant antagonism of endothelial and vascular smooth muscle cell ETB receptors for endothelin induces hypertension in the hamster Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1258 - H1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Just, A. J. M. Olson, J. R. Falck, and W. J. Arendshorst NO and NO-independent mechanisms mediate ETB receptor buffering of ET-1-induced renal vasoconstriction in the rat Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1168 - R1177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Kurtz, K. A. Griffin, A. K. Bidani, R. L. Davisson, and J. E. Hall Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 2: Blood Pressure Measurement in Experimental Animals. A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): e22 - e33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Kurtz, K. A. Griffin, A. K. Bidani, R. L. Davisson, and J. E. Hall Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 2: Blood Pressure Measurement in Experimental Animals: A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Hypertension, February 1, 2005; 45(2): 299 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Williams, J. S. Pollock, and D. M. Pollock Arterial Pressure Response to the Antioxidant Tempol and ETB Receptor Blockade in Rats on a High-Salt Diet Hypertension, November 1, 2004; 44(5): 770 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Plusczyk, B. Witzel, M. D. Menger, and M. Schilling ETA and ETB receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury Am J Physiol Gastrointest Liver Physiol, June 9, 2003; 285(1): G145 - G153. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
