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CARDIOVASCULAR

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-L-tyrosine Peroxisome Proliferator-Activated Receptor- Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (S.M.G., T.B.); and GlaxoSmithKline, Research Triangle Park, North Carolina (D.J.R.N., P.G.B., K.K.B.)

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor- activator, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], 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, hyperemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the ₂-adrenoceptor antagonist, ICI 118551 ((±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride), and was still apparent in the presence of the -adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT₁) and endothelin (ET_A and ET_B) 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 nonselective 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 - or ₂-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.

Address correspondence to: Professor Sheila M. Gardiner, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: sheila.gardiner{at}nottingham.ac.uk

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