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

Abstract

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 ((Ϯ)-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 (AT 1 ) 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.The thiazolidinediones were shown to enhance insulin sensitivity before it was known that they were activators of PPAR-␥ (Spiegelman, 1998;Willson et al., 2000Willson et al., , 2001Rosen and Spiegelman, 2001). Although PPAR-␥ is highly expressed in fat, it occurs in muscle and liver as well, and, to a lesser extent, in tissues of the cardiovascular system (Spiegelman, 1998;Bishop-Bailey, 2000). In the latter context, it is now apparent that the thiazolidinediones may influence cardiovascular function, particularly in patients with diabetes mellitus (Mudaliar and Henry, 2001;Martens et al., 2002), but it is not clear to what extent this involves PPAR-␥-dependent or -independent effects, changes in insulin sensitivity, and/or modulation of inflammatory processes (Spiegelman, 1998;Rosen and Spiegelman, 2001;Klappacher and Glass, 2002;Rival et al., 2002;Shiojiri et al., 2002). Moreover, the acute hemodynamic effects of PPAR-␥ activation in the nondiabetic state have not been described in detail.A novel series of N-(2-benzoylphenyl)-L-tyrosine compounds has been identified as potent PPAR-␥ agonists (Cobb 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).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

“…Second, a PPAR␥ ligand, GI262570, increased expressions of ENaC␣, SGK1, and Na-K-ATPase␣ in the renal medulla (26). Finally, GI262570 caused sodium retention but did not affect glomerular filtration rate, renal plasma flow, and renal filtration fraction (30,31), indirectly supporting the local action of TZDs. In line with these observations, we report that RGZ-induced plasma volume expansion was significantly blunted in PPAR␥ KO mice.…”

PPARγ agonists do not directly enhance basal or insulin-stimulated Na+ transport via the epithelial Na+ channel

“…PPARc is expressed in endothelial and smooth muscle cells [7,21] and receptor activation appears to have direct vasodilatory effects in humans and rodents [5,15,28]. Even with changes in the vasculature, the observed clinical symptoms of salt and water retention suggest a primary or secondary effect on renal salt and water homeostasis.…”

PPARγ Agonist-Induced Fluid Retention Depends on αENaC Expression in Connecting Tubules

“…Fluid retention is an important clinical limitation for TZDs, which occurs in up to 5% of treated diabetic patients, and, as a consequence, these agents are contraindicated in patients with New York Heart Association class III and IV congestive heart failure [3;4]. TZD-induced fluid retention and edema formation has been proposed to involve increases in vascular permeability [4-7] and vasodilation [8;9] as well as primary effects on the kidney. The latter may include an increase in sodium and water reabsorption due to upregulation of various renal transport regulating systems including the Na + -H + exchanger NHE3, the Na-K-2Cl cotransporter NKCC2, the serum/glucocorticoid-regulated kinase 1, the α subunit of Na-K-ATPase, a non-selective cation channel, and/or the water channels aquaporin-2 (AQP-2) and AQP-3 [10-13].…”