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Research ArticleCARDIOVASCULAR

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ 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

Sheila M Gardiner, Derek J. R. Nunez, Philip G. Baer, Kathleen K. Brown and Terence Bennett
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1226-1233; DOI: https://doi.org/10.1124/jpet.104.068817
Sheila M Gardiner
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Derek J. R. Nunez
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Philip G. Baer
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Kathleen K. Brown
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Terence Bennett
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Abstract

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-γ 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 β2-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 α-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 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 α- or β2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.

Footnotes

  • This study was undertaken with financial support from GlaxoSmithKline. Some of the results reported herein have been presented to the British Pharmacological Society (Gardiner et al., 2002a).

  • doi:10.1124/jpet.104.068817.

  • ABBREVIATIONS: PPAR-γ, peroxisome proliferator-activated receptor-γ; GI 262570, (S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid; ICI 118551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride; ZD 7155, 5,7-diethyl-3,4-dihydro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,6-naphthyridin-2(1H)-one hydrochloride; SB 209670, (+)(1S,2R,3S)-3-(carboxymethoxy-4-methoxyphenyl)-1-13,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid; l-NAME, NG-nitro-l-arginine methyl ester; AT1, angiotensin type 1 receptor; ETA or ETB, endothelin type A or B receptor; NO, nitric oxide.

    • Received March 23, 2004.
    • Accepted May 3, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleCARDIOVASCULAR

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ 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

Sheila M Gardiner, Derek J. R. Nunez, Philip G. Baer, Kathleen K. Brown and Terence Bennett
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1226-1233; DOI: https://doi.org/10.1124/jpet.104.068817

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Research ArticleCARDIOVASCULAR

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ 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

Sheila M Gardiner, Derek J. R. Nunez, Philip G. Baer, Kathleen K. Brown and Terence Bennett
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1226-1233; DOI: https://doi.org/10.1124/jpet.104.068817
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