This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bird, J. E. Articles by Powell, J. R. Search for Related Content PubMed PubMed Citation Articles by Bird, J. E. Articles by Powell, J. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Blood Pressure Medicines

(Hypertension. 1995;25:1191-1195.)
© 1995 American Heart Association, Inc.

Articles

Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

J. Eileen Bird; Suzanne Moreland; Thomas L. Waldron; James R. Powell

From the Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Eileen Bird, DVM, PhD, Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000. E-mail bird@ bms.com.

Abstract Endothelin is a potent pressor agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension. BMS-182874 specifically inhibited the pressor response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED₂₅=8 µmol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)–salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA-salt hypertensive rats when administered at a dose of 30, 100, or 300 µmol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 µmol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 µmol/kg) elicited a sustained decrease in blood pressure in the DOCA-salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 µmol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely to be important in all hypertensive states.

Key Words: hypertension, experimental • hypertension, mineralocorticoid • receptors, endothelin • endothelins

This article has been cited by other articles:

				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]

				C. Di Filippo, F. Rossi, E. Ongini, P. Del Soldato, M. Perretti, and M. D'Amico The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1133 - 1141. [Abstract] [Full Text] [PDF]

				M. C. Kowala, N. Murugesan, J. Tellew, K. Carlson, H. Monshizadegan, C. Ryan, Z. Gu, B. Kane, L. Fadnis, R. A. Baska, et al. Novel Dual Action AT1 and ETA Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 275 - 284. [Abstract] [Full Text]

				G. P. Rossi, M. Cavallin, A. S Belloni, G. Mazzocchi, G. G Nussdorfer, A. C Pessina, and S. Sartore Aortic smooth muscle cell phenotypic modulation and fibrillar collagen deposition in angiotensin II-dependent hypertension Cardiovasc Res, July 1, 2002; 55(1): 178 - 189. [Abstract] [Full Text] [PDF]

				Y. Matsumura, T. Kuro, Y. Kobayashi, F. Konishi, M. Takaoka, J. L. Wessale, T. J. Opgenorth, C. E. Gariepy, and M. Yanagisawa Exaggerated Vascular and Renal Pathology in Endothelin-B Receptor-Deficient Rats With Deoxycorticosterone Acetate-Salt Hypertension Circulation, November 28, 2000; 102(22): 2765 - 2773. [Abstract] [Full Text] [PDF]

				G. A. Reinhart, L. C. Preusser, T. J. Opgenorth, C. D. Wegner, and B. F. Cox Endothelin and ETA receptors in long-term arterial pressure homeostasis in conscious nonhuman primates Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1701 - R1706. [Abstract] [Full Text] [PDF]

				G. P. Rossi, A. Sacchetto, D. Rizzoni, S. Bova, E. Porteri, G. Mazzocchi, A. S. Belloni, M. Bahcelioglu, G. G. Nussdorfer, and A. C. Pessina Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid-Independent Mechanisms Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 949 - 956. [Abstract] [Full Text] [PDF]

				D. M. Pollock, G. H. Allcock, A. Krishnan, B. D. Dayton, and J. S. Pollock Upregulation of endothelin B receptors in kidneys of DOCA-salt hypertensive rats Am J Physiol Renal Physiol, February 1, 2000; 278(2): F279 - F286. [Abstract] [Full Text] [PDF]

				D. L. Lange, J. R. Haywood, and C. Hinojosa-Laborde Endothelin Enhances and Inhibits Adrenal Catecholamine Release in Deoxycorticosterone Acetate-Salt Hypertensive Rats Hypertension, January 1, 2000; 35(1): 385 - 390. [Abstract] [Full Text] [PDF]

				M. M. Muthalif, I. F. Benter, Z. Khandekar, L. Gaber, A. Estes, S. Malik, J.-H. Parmentier, V. Manne, and K. U. Malik Contribution of Ras GTPase/MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt-Induced Hypertension Hypertension, January 1, 2000; 35(1): 457 - 463. [Abstract] [Full Text] [PDF]

				K. Munter, H. Ehmke, and M. Kirchengast Maintenance of blood pressure in normotensive dogs by endothelin Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1022 - H1027. [Abstract] [Full Text] [PDF]

				G. H. Allcock, R. C. Venema, and D. M. Pollock ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R245 - R252. [Abstract] [Full Text] [PDF]

				D. L. Lange, J. R. Haywood, and C. Hinojosa-Laborde Role of the Adrenal Medullae in Male and Female DOCA-Salt Hypertensive Rats Hypertension, January 1, 1998; 31(1): 403 - 408. [Abstract] [Full Text] [PDF]

				P. Moreau, H. Takase, C. F. Kung, S. Shaw, and T. F. Luscher Blood Pressure and Vascular Effects of Endothelin Blockade in Chronic Nitric Oxide–Deficient Hypertension Hypertension, March 1, 1997; 29(3): 763 - 769. [Abstract] [Full Text]

				P. Sventek, A. Turgeon, and E. L. Schiffrin Vascular Endothelin-1 Gene Expression and Effect on Blood Pressure of Chronic ETA Endothelin Receptor Antagonism After Nitric Oxide Synthase Inhibition With L-NAME in Normal Rats Circulation, January 7, 1997; 95(1): 240 - 244. [Abstract] [Full Text]

				K. Skov, J. Fenger-Gron, and M. J. Mulvany Effects of an Angiotensin-Converting Enzyme Inhibitor, a Calcium Antagonist, and an Endothelin Receptor Antagonist on Renal Afferent Arteriolar Structure Hypertension, September 1, 1996; 28(3): 464 - 471. [Abstract] [Full Text]

				B. Bartholomeusz, K. J. Hardy, A. S. Nelson, and P. A. Phillips Bosentan Ameliorates Cyclosporin A–Induced Hypertension in Rats and Primates Hypertension, June 1, 1996; 27(6): 1341 - 1345. [Abstract] [Full Text]