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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 6, 2006; DOI: 10.1124/jpet.106.106781

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Received for publication April 25, 2006.
Revised May 31, 2006.
Accepted for publication June 26, 2006.

REGIONAL HEMODYNAMIC EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION AND ANGIOTENSIN (AT1) RECEPTOR ANTAGONISM ALONE OR IN COMBINATION IN CONSCIOUS SHR

Sheila Gardiner 1*, Julie March 1, Philip Kemp 1, Stephen Ballard 2, Terence Bennett 1

1 University of Nottingham 2 Pfizer Global Research & Development

* Address correspondence to: E-mail: sheila.gardiner{at}nottingham.ac.uk

Abstract

We tested the hypothesis that angiotensin (AT1) receptor antagonism (with losartan) would enhance the cardiovascular actions of neutral endopeptidase (NEP) inhibition (with candoxatrilat or UK-489,329) in conscious SHR. Four day continuous intravenous infusion of candoxatrilat (1.9 µg kg-1 min-1) or UK-489,329 (0.15 µg kg-1 min-1), had no significant cardiovascular effects, whereas candoxatrilat (6.4 µg kg-1 min-1) had a modest antihypertensive effect (-10.9 mmHg on Day 4), but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum 29.2 mm Hg on Day 4) that was associated with renal, mesenteric and, to a lesser extent hindquarters vasodilatation. The combination of losartan with either dose of candoxatrilat had no greater antihypertensive or vasodilator effects than losartan alone, with the exception of the increase in renal vascular conductance, which was greater with the combination of the drugs than with either drug alone (significant only in the lower dose study). Losartan combined with UK-489,329 showed a greater antihypertensive effect than losartan alone (-14.6mm Hg greater on Day 4), although the effects of the combination were not significantly greater than the sum of the effects of both agents administered separately. However, losartan combined with UK-489,329 caused increases in renal and hindquarters vascular conductance that were significantly greater with the combination than with either agent given alone. Thus, in conscious SHR, the renin-angiotensin system may act to oppose a vasodilator action of NEP inhibition, particularly in the renal vascular bed.


Key words: angiotensin receptor blocker, blood pressure, hemodynamics, neutral endopeptidase inhibition, spontanously hypertensive rat, vasopeptidase inhibition




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