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A‐272651, a nonpeptidic blocker of large‐conductance Ca 2+ ‐activated K + channels, modulates bladder smooth muscle contractility and neuronal action potentials
Author(s) -
Shieh CC,
Turner S C,
Zhang XF,
Milicic I,
Parihar A,
Jinkerson T,
Wilkins J,
Buckner S A,
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.0707278
Subject(s) - bk channel , iberiotoxin , chemistry , detrusor muscle , patch clamp , contraction (grammar) , contractility , biophysics , channel blocker , endocrinology , medicine , electrophysiology , membrane potential , urinary bladder , calcium , biology , biochemistry , organic chemistry
Background and Purpose: The large‐conductance Ca 2+ ‐activated K + channel (BK Ca , K Ca 1.1) links membrane excitability with intracellular Ca 2+ signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK Ca channel blocker, 2,4‐dimethoxy‐N‐naphthalen‐2‐yl‐benzamide (A‐272651). Experimental Approach: 86 Rb + efflux in HEK‐293 cells expressing BK Ca was measured. Effects of A‐272651 on BK Ca α‐ and BK Ca αβ1‐mediated currents were evaluated by patch‐clamp. Effects on contractility were assessed using low‐frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A‐272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG). Key Results: A‐272651 (10 μM) inhibited 86 Rb + efflux evoked by NS‐1608 in HEK‐293 cells expressing BK Ca currents. A‐272651 concentration‐dependently inhibited BK Ca currents with IC 50 values of 4.59 μM (Hill coefficient 1.04, measured at +40 mV), and 2.82 μM (Hill coefficient 0.89), respectively, for BK Ca α and BK Ca αβ1‐mediated currents. Like iberiotoxin, A‐272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC 50 values of 4.05±0.05 and 37.95±0.12 μM, respectively. In capsaicin‐sensitive DRG neurons, application of A‐272651 increased action potential firing and prolonged action potential duration. Conclusions and Implications: These data demonstrate that A‐272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BK Ca blockers, A‐272651 represents one of the first small molecule BK Ca channel blockers that could serve as a useful tool for further characterization of BK Ca channels in physiological and pathological states. British Journal of Pharmacology (2007) 151 , 798–806; doi: 10.1038/sj.bjp.0707278