The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism

EH Ohlstein, M Gellai, DP Brooks, L Vickery, J Jugus, A Sulpizio, RR Ruffolo , J Weinstock and RM Edwards

Department of Pharmacology, SmithKline Beecham Research Laboratories, King of Prussia, Pennsylvania.

The angiotensin II (AII) receptor antagonist, DuP 753 (10 mg/kg intraduodenal), produced a sustained and long-lasting antihypertensive effect in conscious renin-dependent hypertensive rats. Blood pressures were still reduced markedly 24 to 72 hr after administration of a single dose of DuP 753. However, pressor responses elicited by either angiotensin I or AII were not blocked at these times despite the continued antihypertensive effect of DuP 753. In a model of orthostatic hypotension, DuP 753 and the selective alpha-1 adrenoceptor antagonist prazosin produced a marked orthostatic hypotension response in renin- dependent hypertensive rats as demonstrated by potentiation of the decrease in blood pressure induced by a 90 degrees tilt. The nonpeptide AII receptor antagonist SK&F 108566 (10 mg/kg intraduodenal) did not produce orthostatic hypotension and the angiotensin converting enzyme inhibitor enalapril produced only a slight orthostatic response to tilting. In conscious spontaneously hypertensive rats (SHR), allowed 3 to 4 days to recover from surgery, administration of either enalapril (1 mg/kg i.v.) or SK&F 108566 (10 mg/kg i.v.) did not significantly effect blood pressure. In SHR tested within 24 hr of surgery, enalapril was effective in lowering blood pressure. In contrast, in surgically recovered SHR, DuP 753 (10 mg/kg i.v.) produced an antihypertensive effect that was slow in onset, sustained and extremely long in duration. Blood pressures did not return to predrug levels until 48 hr after administration of DuP 753. Stimulation of the thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses that were significantly potentiated by continuous infusion of a subpressor dose of AII.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 262, Issue 2, pp. 595-601, 08/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				L. Kalinowski, T. Matys, E. Chabielska, W. Buczko, and T. Malinski Angiotensin II AT1 Receptor Antagonists Inhibit Platelet Adhesion and Aggregation by Nitric Oxide Release Hypertension, October 1, 2002; 40(4): 521 - 527. [Abstract] [Full Text] [PDF]

				S. Ye, H. Zhong, V. N. Duong, and V. M. Campese Losartan Reduces Central and Peripheral Sympathetic Nerve Activity in a Rat Model of Neurogenic Hypertension Hypertension, June 1, 2002; 39(6): 1101 - 1106. [Abstract] [Full Text] [PDF]

				C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]

				M. Morris, S. Means, M. I. Oliverio, and T. M. Coffman Enhanced central response to dehydration in mice lacking angiotensin AT1a receptors Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R1177 - R1184. [Abstract] [Full Text] [PDF]

				K. Inoue, H. Nishimura, J. Kubota, and Y. Kitaura Nitric oxide mediates inhibitory effect of losartan on angiotensin-induced contractions in hamster but not rat aorta Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 180 - 183. [Abstract] [PDF]

				V. M Campese, Shaohua Ye, R. H Truong, and M. Gamburd Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 202 - 208. [Abstract] [PDF]

				P. Li, M. Fukuhara, D. I. Diz, C. M. Ferrario, and K. B. Brosnihan Novel Angiotensin II AT1 Receptor Antagonist Irbesartan Prevents Thromboxane A2-Induced Vasoconstriction in Canine Coronary Arteries and Human Platelet Aggregation J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 238 - 246. [Abstract] [Full Text]

				P. Li, C. M. Ferrario, and K. B. Brosnihan J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1065 - 1070. [Abstract] [Full Text]

				V. Cachofeiro, R. Maeso, E. Rodrigo, J. Navarro, L. M. Ruilope, and V. Lahera Nitric Oxide and Prostaglandins in the Prolonged Effects of Losartan and Ramipril in Hypertension Hypertension, August 1, 1995; 26(2): 236 - 243. [Abstract] [Full Text]

				C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]