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Characterization of a novel ATP‐sensitive K + channel opener, A‐251179, on urinary bladder relaxation and cystometric parameters
Author(s) -
Shieh CC,
Brune M E,
Buckner S A,
Whiteaker K L,
Molinari E J,
Milicic I A,
Fabiyi A C,
Daza A,
Brioni J D,
Carroll W A,
Matsushita K,
Yamada M,
Kurachi Y,
Gopalakrishnan M
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707249
Subject(s) - pinacidil , contractility , carbachol , urinary bladder , isovolumetric contraction , chemistry , potassium channel opener , in vivo , cystometry , contraction (grammar) , muscle contraction , detrusor muscle , muscle relaxation , stimulation , endocrinology , pharmacology , medicine , potassium channel , glibenclamide , blood pressure , biology , microbiology and biotechnology , diastole , diabetes mellitus
Background and Purpose: ATP‐sensitive K + channels (K ATP ) play a pivotal role in contractility of urinary bladder smooth muscle. This study reports the characterization of 4‐methyl‐N‐(2,2,2‐trichloro‐1‐(3‐pyridin‐3‐ylthioureido)ethyl)benzamide (A‐251179) as a K ATP channel opener. Experimental Approach: Glyburide‐sensitive membrane potential, patch clamp and tension assays were employed to study the effect of A‐251179 in vitro . The in vivo efficacy of A‐251179 was characterized by suppression of spontaneous contractions in obstructed rat bladder and by measuring urodynamic function of urethane‐anesthetized rat models. Key Results: A‐251179 was about 4‐fold more selective in activating SUR2B‐Kir6.2 derived K ATP channels compared to those derived from SUR2A‐Kir6.2. In pig bladder smooth muscle strips, A‐251179 suppressed spontaneous contractions, about 27‐ and 71‐fold more potently compared to suppression of contractions evoked by low‐frequency electrical stimulation and carbachol, respectively. In vivo , A‐251179 suppressed spontaneous non‐voiding bladder contractions from partial outlet‐obstructed rats. Interestingly, in the neurogenic model where isovolumetric contractions were measured by continuous transvesical cystometry, A‐251179 at a dose of 0.3 μmol kg ‐1 , but not higher, was found to increase bladder capacity without affecting either the voiding efficiency or changes in mean arterial blood pressure. Conclusions and Implications: The thioureabenzamide analog, A‐251179 is a potent novel K ATP channel opener with selectivity for SUR2B/Kir6.2 containing K ATP channels relative to pinacidil. The pharmacological profile of A‐251179 is to increase bladder capacity and to prolong the time between voids without affecting voiding efficiency and represents an interesting characteristic to be explored for further investigations of K ATP channel openers for the treatment of overactive bladder. British Journal of Pharmacology (2007) 151 , 467–475; doi: 10.1038/sj.bjp.0707249