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 beta(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 alpha-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT(1)) 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 beta(2)-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.

PPARgamma agonists ameliorate insulin resistance and lower blood pressure. Volume expansion/edema has been observed in susceptible patients treated with these agents. Alterations of renal hemodynamics affect renal tubular reabsorption, and thus may contribute to volume expansion. This study seeks to determine whether volume expansion caused by a PPARgamma agonist, GI262570, is related to changes in glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. Chronically catheter-implanted conscious rats were studied to determine the effects on glomerular filtration rate, effective renal plasma flow, and renal filtration fraction after 1, 4, and 10 days of GI262570 treatment (8 mg/kg, p.o., B.I.D.). Elevated adipose mRNA of PPARgamma target genes confirmed PPARgamma activation in GI262570-treated rats. GI262570 treatment for 10 days decreased hematocrit, hemoglobin, and serum albumin (all P < 0.05), indicating volume expansion, but did not alter glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. However, nitrate + nitrite was significantly higher in plasma and hind limb muscle of GI262570-treated rats (both P < 0.05). This study demonstrated that treatment with PPARgamma agonist GI262570 resulted in volume expansion and increased nitric oxide, but did not affect glomerular filtration rate, effective renal plasma flow, or renal filtration fraction, indicating PPARgamma agonist-induced volume expansion is not related to changes in renal filtration fraction, and increased nitric oxide may contribute to the PPARgamma agonist-induced blood-pressure lowering.

PURPOSE:Varying the concentration of infused acetic acid produced bladder irritation and dose dependent increases in external urethral sphincter electromyography activity in cats. We further characterized acetic acid induced external urethral sphincter electromyography activity in intact and acute spinal cord injured animals. MATERIALS AND METHODS:Bladder cystometrography and external urethral sphincter electromyography were continuously recorded in chloralose anesthetized cats. Dilute 0.05% to 0.8% acetic acid was infused into the lower urinary tract through the bladder dome. Intravesical or intraurethral infusion was performed separately in bladder neck ligated preparations. In some animals the spinal cord was transected at L1 to L2 2 to 8 hours before the study. RESULTS:Acetic acid infusion into the lower urinary tract elicited dose dependent increases in tonic external urethral sphincter activity. However, a prolonged infusion of 0.7% to 0.8% acetic acid usually inhibited external urethral sphincter activity. The excitatory external urethral sphincter response was elicited by intraurethral but not by intravesical infusion. This response remained in acute spinal cord injured animals. The inhibition of tonic external urethral sphincter activity during 0.7% to 0.8% acetic acid infusion was observed when there was extreme bladder irritation characterized by continual contractions. Induced tonic external urethral sphincter activity was attenuated by intrathecal administration of prazosin or scopolamine and abolished by hexamethonium. CONCLUSIONS:Acetic acid infusion into the lower urinary tract elicits biphasic external urethral sphincter responses. The early excitatory response is a spinal urethrourethral reflex and the late inhibitory phase results from negative vesicourethral feedback control. Spinal muscarinic cholinergic and alpha-adrenergic receptors are involved in acetic acid induced excitatory external urethral sphincter responses.

The utility of the bone targeting 4-carboxy-3-hydroxy-1,2-pyrazole heterocycle was tested by the synthesis of hybrids with the non-steroidal estrogen hexestrol. Compounds 1 and 2 demonstrated significant hydroxyapatite affinity, while maintaining weak estrogenic activity in whole cell assays.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic Acid: A Non-Steroidal Estrogen with Functional Selectivity for Bone over Uterus in RatsTimothy M. Willson, Brad R. Henke, Tanya M. Momtahen, Paul S. Charifson, Kenneth W. Batchelor, Dennis B. Lubahn, Linda B. Moore, Beverly B. Oliver, Howard R. Sauls, James A. Triantafillou, Steven G. Wolfe, and Philip G. BaerCite this: J. Med. Chem. 1994, 37, 11, 1550–1552Publication Date (Print):May 1, 1994Publication History Published online1 May 2002Published inissue 1 May 1994https://pubs.acs.org/doi/10.1021/jm00037a002https://doi.org/10.1021/jm00037a002research-articleACS PublicationsRequest reuse permissionsArticle Views409Altmetric-Citations124LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts