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Comparison of the vascular and antiadrenergic activities of four angiotensin II type 1 antagonists in the pithed rat

Dendorfer, Andreas; Raasch, Walter; Tempel, Klaus; Dominiak, Peter

Original papers: Renin-angiotensin system

Background  Angiotensin II is known to facilitate the release of catecholamines from peripheral sympathetic neurons by stimulating presynaptically located receptors. Although inhibitor studies have revealed these to be angiotensin II type 1 (AT1) receptors, they do in fact appear to display peculiar susceptibilities to various AT1 receptor antagonists, which might correspond to different neuronal and vascular receptor subtypes.

Objective  A direct comparison of the pre- and postsynaptic potencies of four AT1 antagonists was performed to characterize these receptors further.

Design  We studied angiotensin II-induced catecholamine release and vasoconstriction in pithed, spontaneously hypertensive rats under the influence of candesartan, eprosartan, EXP 3174, and irbesartan. The effect of AT1 blockade on postsynaptic vascular sensitivity to noradrenaline (NA) was also determined.

Methods  Pithed rats received repeated intravenous applications of either angiotensin II or NA, preceded by cumulatively increasing doses of the AT1 antagonists. Vasoconstriction and catecholamine release were quantified by the measurement of acute increases in blood pressure and plasma NA, respectively.

Results  All AT1 antagonists dose-dependently suppressed angiotensin II-induced vasoconstriction and release of NA. Although the antagonists differed greatly in their inhibitory potencies (ID50 range 7–445 μg/kg), each displayed a similar potency at both neuronal and vascular angiotensin receptors. In a higher dose range, all AT1 antagonists attenuated the blood pressure increase in response to NA by up to 70%. The order of potencies for all inhibitory effects was: candesartan > eprosartan > EXP 3174 > irbesartan.

Conclusion  The AT1 antagonists tested do not discriminate between presynaptic neuronal and postsynaptic vascular angiotensin II receptors – a fact that refutes the existence of tissue-specific AT1 receptor subtypes. A marked reduction in vascular sensitivity to NA may contribute to the antihypertensive and cardioprotective mechanisms of AT1 antagonists.

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.

Note: Parts of this work have been published as an abstract (Dendorfer A, Raasch W, Tempel K, Dominiak P. Pre- and postsynaptic activities of four AT1-antagonists in SHR. J Renin Angiotensin Aldosterone Syst 2000;1:91).

Sponsorship: The following companies supported this study by supplying grants or test substances: AstraZeneca, Wedel, Germany; Bristol-Myers Squibb, München, Germany; MSD Sharp & Dohme, München, Germany; SmithKline Beecham Pharma, München, Germany.

Correspondence and requests for reprints to Andreas Dendorfer MD, Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel: +49 451 5002684; fax: +49 451 5003327; e-mail: dendorfe@medinf.mu-luebeck.de

Received 15 October 2001

Revised 14 December2001

Accepted 25 January 2002

See editorial commentary page 1061

© 2002 Lippincott Williams & Wilkins, Inc.