Regional hemodynamic effects of the N-(2-benzoylphenyl)-L-tyrosine peroxisome proliferator-activated receptor-gamma 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.
This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-gamma 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 beta2-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 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 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 alpha- or beta2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.
Gardiner
Sheila M
SM
Centre for Integrated Systems Biology, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. sheila.gardiner@nottingham.ac.uk
Nunez
Derek J R
DJ
Baer
Philip G
PG
Brown
Kathleen K
KK
Bennett
Terence
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006439:Hemodynamics / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology*
D007189:Indans; D009287:Naphthyridines; D010080:Oxazoles; D011412:Propanolamines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C095905:ZD 7155; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D009569:Nitric Oxide; C422415:farglitazar; D014443:Tyrosine; C026777:ICI 118551; D008729:Methoxamine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D010646:Phentolamine