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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 4, 2004; DOI: 10.1124/jpet.104.068817

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Received for publication March 23, 2004.
Revised March 23, 2004.
Accepted for publication May 3, 2004.

Regional hemodynamic effects of the N-(2-benzoylphenyl)-L-tyrosine peroxisome proliferator-activated receptor (PPAR) -{gamma}-ligand, GI 262570, in conscious rats

Sheila M Gardiner 1*, Derek J Nunez 2, Philip Baer 2, Kathleen Brown 2, Terence Bennett 1

1 University of Nottingham 2 GSK

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

Abstract

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor (PPAR) -{gamma} activator, GI 262570, in conscious, male, Sprague-Dawley rats. Administration of GI 262570 twice daily for 4 days caused a slowly-developing, modest, fall in mean arterial blood pressure, associated with a progressive, hyperaemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the {beta}2-adrenoceptor antagonist, ICI 118551, and was still apparent in the presence of the {alpha}-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT1) and endothelin (ETA and ETB) receptors unmasked vasodilator responses to GI 262570 in the renal or mesenteric vascular beds. In the presence of GI 262570, vasodilator responses to acetylcholine, and vasoconstrictor responses to methoxamine were normal. Furthermore, the cardiovascular responses to non-selective nitric oxide synthase inhibition were not influenced by GI 262570. Collectively, these results indicate that the vasodilator action of GI 262570 is specific to the hindquarters vascular bed (of those studied), does not involve {alpha}- or {beta}2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.


Key words: PPAR gamma, angiotensin II, endothelin, hemodynamics, nitric oxide, vasodilatation


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