(−)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization

Gopalakrishnan, Murali; Buckner, Steven A.; Whiteaker, Kristi L.; Shieh, Char‐Chang; Molinari, Eduardo J.; Milicic, Ivan; Daza, Anthony V.; Davis-Taber, Rachel; Scott, Victoria E.; Sellers, Donna; Chess-Williams, Russ; Chapple, Christopher R.; Liu, Yi; Liu, Dong; Brioni, Jorge D.; Sullivan, James P.; Williams, Michael B.; Carroll, William A.; Coghlan, Michael J.

doi:10.1124/jpet.102.034538

Cited by 32 publications

(16 citation statements)

References 36 publications

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“…Among them, the large conductance voltage- and Ca 2+ -activated K + channels (BK Ca or K Ca 1.1 channels) are recognised as key regulators of excitability and contractility of the DSM [24]. The SK Ca channels (K Ca 2.1–K Ca 2.3) and K ATP channel have also been reported to induce hyperpolarization and to decrease contractibility in urinary bladder smooth muscle from human and guinea-pig [25], [26]. Inhibition of muscarinic contractions by menthol could occur through opening of smooth muscle K + channels to cause K + efflux, hyperpolarisation and subsequent relaxation.…”

Section: Discussionmentioning

confidence: 99%

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

et al. 2014

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Agonists such as icilin and menthol can activate the cool temperature-sensitive ion channel TRPM8. However, biological responses to menthol may occur independently of TRPM8 activation. In the rodent urinary bladder, menthol facilitates the micturition reflex but inhibits muscarinic contractions of the detrusor smooth muscle. The site(s) of TRPM8 expression in the bladder are controversial. In this study we investigated the regulation of bladder contractility in vitro by menthol. Bladder strips from wild type and TRPM8 knockout male mice (25–30 g) were dissected free and mounted in organ baths. Isometric contractions to carbachol (1 nM–30 µM), CaCl2 (1 µM to 100 mM) and electrical field stimulation (EFS; 8, 16, 32 Hz) were measured. Strips from both groups contracted similarly in response to both carbachol and EFS. Menthol (300 µM) or nifedipine (1 µM) inhibited carbachol and EFS-induced contractions in both wild type and TRPM8 knockout bladder strips. Incubation with the sodium channel blocker tetrodotoxin (1 µM), replacement of extracellular sodium with the impermeant cation N-Methyl-D-Glucamine, incubation with a cocktail of potassium channel inhibitors (100 nM charybdotoxin, 1 µM apamin, 10 µM glibenclamide and 1 µM tetraethylammonium) or removal of the urothelium did not affect the inhibitory actions of menthol. Contraction to CaCl2 was markedly inhibited by either menthol or nifedipine. In cultured bladder smooth muscle cells, menthol or nifedipine abrogated the carbachol or KCl-induced increases in [Ca2+]i. Intravesical administration of menthol increased voiding frequency while decreasing peak voiding pressure. We conclude that menthol inhibits muscarinic bladder contractions through blockade of L-type calcium channels, independently of TRPM8 activation.

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Section: Discussionmentioning

confidence: 99%

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

et al. 2014

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“…ZM244085 and A-278637, compounds belonging to the category of ATP-sensitive K ϩ channel openers, have been shown to relax urinary bladder smooth muscle strips by activating ATP-sensitive potassium current (Li et al, 1996;Brune et al, 2002;Gopalakrishnan et al, 2002). Systematic chemical modification of the dihydropyridine core has led to the identification of A-312110 (Fig.…”

Section: Discussionmentioning

confidence: 99%

[¹²⁵I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K⁺Channel Opener: Characterization and Pharmacology of Binding

Davis-Taber

Molinari²,

Altenbach³

et al. 2003

Mol Pharmacol

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“…A-278637 was comprehensively characterized both in vitro [86] and in vivo [87]. It activated K ATP channels in bladder smooth muscle cells with an EC 50 of 102 nM.…”

Section: Dhp-related Structuresmentioning

confidence: 99%

“…Effects on low and high KCl induced contractions, 86 Rb efflux, and [ 3 H]P1075 binding in guineapig bladder strips were used to characterize its in vitro KCO properties [83]. ZM-244085 possesses in vivo bladder selectivity [84].…”

Section: Dhp-related Structuresmentioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs) e.g. relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. Structure-activity relationships of the main chemical classes of KCOs are discussed.

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(−)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization

Cited by 32 publications

References 36 publications

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

[¹²⁵I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K⁺Channel Opener: Characterization and Pharmacology of Binding

Structure-Activity Relationships of KATP Channel Openers

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(−)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization

Cited by 32 publications

References 36 publications

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

Menthol Inhibits Detrusor Contractility Independently of TRPM8 Activation

[125I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K+Channel Opener: Characterization and Pharmacology of Binding

Structure-Activity Relationships of KATP Channel Openers

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[¹²⁵I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K⁺Channel Opener: Characterization and Pharmacology of Binding