The present study describes the bladder-relaxant properties of LDD175 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo [3,2-b]indole-1-carboxylic acid), a novel benzofuroindole compound. LDD175 had no significant effect on the spontaneous and electrically evoked bladder contractions, but produced concentration-dependent relaxation in strips precontracted by 1 micromol/l acetylcholine (pEC(50) = 5.9 +/- 0.2, E(max) = 90.3 +/- 2.6%; 100 micromol/l, n = 6). In high K(+)- (20 and 80 mmol/l) stimulated samples, LDD175 caused a concentration-dependent relaxant activity which was significant in 20 mmol/l K(+) (pEC(50) = 5.6 +/- 0.2, E(max) = 63.1 +/- 4.8%, n = 6), but not in 80 mmol/l K(+) (pEC(50) = 5.1 +/- 0.3, E(max) = 12.7 +/- 2.5%, n = 6). Iberiotoxin (100 nmol/l), a specific BKCa blocker, attenuated the compound's relaxative effect (vehicle = 65.7 +/- 9.2% vs. iberiotoxin 28.0 +/- 3.5%, respectively, n = 3), but not tetraethylammonium chloride (10 mmol/l), a nonselective K(+) channel blocker, barium chloride (10 mmol/l), a conventional K(IR) blocker, and glibenclamide (1 mmol/l), a K(ATP) blocker. LDD175 was evaluated in both endothelium-intact and denuded rat aorta contracted with high K(+). In these preparations, LDD175 did not produce significant inhibition. Administered intravenously to conscious restrained rats, LDD175 (10 mg/kg) did not alter the rat's hemodynamic activity (i.e. blood pressure and heart rate). When tested in the spontaneously hypertensive rats (SHR) for its influence on their voiding behavior, LDD175 (5 and 10 mg/kg) significantly reduced voiding frequency and lengthened void intervals of the animals. These observations: (1) reveal the BKCa channel potentiation of LDD175; (2) support previous claims concerning the bladder (vs. vascular) selectivity of benzofuroindole compounds; (3) demonstrate the efficacy of LDD175 in the animal model of bladder overactivity (SHR). Therefore, the compound may be potentially useful in the treatment of bladder overactivity.
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http://dx.doi.org/10.1159/000218739 | DOI Listing |
ACS Omega
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Laboratório de Bioinformática e Química Medicinal, Fundação Oswaldo Cruz Rondônia, Porto Velho, Rondônia 76812-245, Brazil.
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Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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January 2025
Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
The chemokine-like receptor 1 (CMKLR1) is activated by the adipokine and chemoattractant protein chemerin. Cryo-EM structures of chemerin-9-CMKLR1-Gi have been published, where chemerin-9 is the nonapeptide of the C terminus of chemerinS157. Chemerin-9 is as active as the full-length protein in Ca-release but shows differences in equilibrium read-outs.
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Servicio de Histología-Investigación. Unidad de Investigación Traslacional en Cardiología-IRYCIS/UFV, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
The identification of obese subjects at higher risk for cardiovascular disease (CVD) is required. We aimed to characterize determinants of endothelial dysfunction, the initial step to CVD, in small omental arteries of visceral fat from obese subjects. The influences of analytical parameters and vascular oxidative stress mediated by NADPH-oxidase-2 (NOX2) on endothelial function were determined.
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October 2024
Postgraduate Program in Biosciences, Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil.
(-)-Carvone, a ketone monoterpene, is the main component of essential oils from several medicinal plants and has been reported to have anti-arthriric, anticonvulsive, antidiabetic, anti-inflammatory, anticancer, and immunomodulatory effects. Therefore, this study aimed to investigate the spasmolytic activity of (-)-carvone in rodent models. The isolated virgin rat uterus was mounted in an organ bath apparatus, and the relaxing effect of ( -)-carvone and its mechanism of action were evaluated in tonic contractions induced by carbachol, KCl, PGF, or oxytocin.
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