The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant binding of muscarinic receptors in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M3 subtype. Oral tolterodine binds more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic receptor binding in the bladder. In vivo quantitative autoradiography with (+)N-[11C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration.

Saw palmetto extract attenuates the alteration of urodynamic parameters, pharmacologically relevant receptors, and urinary cytokines in CYP-treated rats. Therefore, SPE may be a potential therapeutic agent for improving the clinical symptoms of cystitis.

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The present study aimed to characterize comparatively endothelin-1 (ET-1) receptors in rat tissues by radioligand binding assay using [125 I]ET-1 and to examine receptor binding after oral administration of bosentan. Significant amount of specific [125 I]ET-1 binding was detected in the lung, heart, kidney, bladder and cerebral cortex of rats. ET-1, bosentan, ambrisentan, and CI-1020 inhibited specific [125 I]ET-1 binding in these tissues in a concentration-dependent manner. The Hill coefficients of each agent in the rat lung and cerebral cortex and those of bosentan and ET-1 in the heart, kidney and bladder were close to unity, while the Hill coefficients of ambrisentan and CI-1020 in the heart, kidney and bladder were less than one. The nonlinear least squares regression analysis revealed the presence of high-and low-affinity ET-1 receptor sites in these tissues for ambrisentan and CI-1020. Oral administration of bosentan caused a dose-dependent decrease in specific [125 I]ET-1 binding in the rat lung, kidney and bladder, suggesting significant binding of the tissue ET-1 receptors in vivo. In conclusion, it has been shown that a significant amount of pharmacologically relevant ET-1 receptors may exist in rat tissues and that ET-1 receptor antagonists such as bosentan at pharmacological doses may exert some pharmacological effects by binding these ET-1 receptors.Key words endothelin-1 receptor; rat tissue; bosentan; ambrisentan; CI-1020; receptor binding characteristics Endothelin-1 (ET-1) was isolated from the culture media of porcine aortic endothelial cells as the most potent vasoconstrictive peptide identified to date.1) ET-1 is synthesized by both vascular and non-vascular smooth muscle cells.2) In addition to producing potent contractions in vascular smooth muscle, ET-1 can also produce contractions in non-vascular smooth muscles including the urinary bladder.3-8) The biological effects of endothelins are mediated through the specific receptors, ET A and ET B .9,10) Both receptor subtypes of ET A and ET B mediate the vasoconstrictor and pressor actions of endothelins. ET-1 receptors have been shown to be present in several non-vascular tissues such as the heart, kidney and bladder, [3][4][5][6][7][8][9][10] but the receptor properties such as the subtype distribution in these tissues have not been characterized simultaneously. Also, the receptor binding of ET-1 receptor antagonists has not been comparatively examined in different tissues.Bosentan, the first non-peptide endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension, is a nonselective ET A and ET B subtype antagonist, [11][12][13] while ambrisentan and CI-1020 are relatively selective of the ET A subtype.12-14) Ambrisentan has also been approved for the treatment of pulmonary arterial hypertension, and has lower hepatotoxicity and weaker drug interaction. 12,13)

Abstract. The present study aimed to characterize bladder endothelin-1 (ET-1) receptor binding of clinically used ET-1 receptor antagonists by using [125 I]ET-1. The inhibition of specific [ 125