The functional effects of NS1608 ((N‐(3‐(trifluoromethyl)phenyl)‐N′‐(2‐hydroxy‐5‐chlorophenyl)urea), an opener of the large conductance, Ca2+‐activated K+ (BKCa) channel, on the contractility of guinea‐pig urinary bladder muscle are described.

NS1608 (0.3–30 μM) had no significant effect on the integrated myogenic activity (tension integral) or the electrically evoked twitches of detrusor muscle strips. Possible mechanisms for the discrepancy between the lack of functional effects of NS1608 per se on detrusor contractility and this drug's agonistic effect on BKCa currents in isolated bladder myocytes are discussed.

4‐Aminopyridine (1 mM), a blocker of voltage‐gated K+ (KV) channels, increased the tension integral 2.7‐fold, on average. NS1608 (30 μM) counteracted this effect.

Apamin (100 nM), a selective blocker of the small conductance, Ca2+‐activated K+ (SKCa) channel, increased the tension integral 1.7‐fold, on average. This effect was reversed by NS1608 (30 μM).

Ryanodine (10 μM), a modulator of the sarcoplasmic reticulum (SR) Ca2+‐release channel, increased the tension integral 1.9‐fold, on average. This effect was reversed by NS1608 (30 μM).

Iberiotoxin (IbTX, 50 nM), a selective blocker of the BKCa channel, caused additional increases in the tension integral of detrusor strips pretreated with apamin or ryanodine and prevented the inhibitory effects of NS1608 (30 μM) in detrusor contractility.

The present study shows that blockade of repolarizing currents carried by, respectively apamin‐ and 4‐aminopyridine‐sensitive K+ channels unmasks an activation of BKCa in guinea‐pig urinary bladder smooth muscle strips.

British Journal of Pharmacology (2005) 144, 636–641. doi:10.1038/sj.bjp.0706034

01 Oct 2003·ASSAY and Drug Development TechnologiesQ4 · MEDICINE

Functional Analysis of Large Conductance Ca2⁺-Activated K⁺ Channels: Ion Flux Studies by Atomic Absorption Spectrometry

Q4 · MEDICINE

Article

Author: Gopalakrishnan, Murali ; Zhang, Xu-Feng ; Shieh, Char-Chang ; Scott, Victoria E. ; Groebe, Duncan R. ; Warrior, Usha ; Parihar, Ashutosh S. ; Feng, Jianlin

Although techniques such as (86)Rb(+) flux provide a sensitive measure of K(+) channel activity, the relatively short half-life and high-energy emission, together with the quantities of radioactive material generated, hinder the usefulness of flux-based formats in high throughput screening efforts. This study elaborates on the utilization of flame atomic absorption spectrometry (AAS) techniques for a nonradioactive rubidium efflux assay for large conductance Ca(2+)-activated K(+) channels (BK(Ca)) channels. Utilizing human embryonic kidney (HEK293) cells expressing the BK(Ca) alpha subunit, a 96-well cell-based nonradioactive rubidium efflux screen for channel openers and inhibitors was established. Known BK(Ca) channel openers, including NS1608, NS1619, and NS-8, activated rubidium efflux with EC(50) values ranging from 1 to 4 microM in both radioactive and nonradioactive efflux formats. Compounds such as iberiotoxin, paxilline, and charybdotoxin inhibited rubidium efflux responses evoked by the BK(Ca) channel opener NS1608 in both radioactive and nonradioactive efflux formats. The IC(50) values of the inhibitors in AAS format were comparable to those derived from (86)Rb(+) efflux assays. The present studies show that the pharmacological profiles of BK(Ca) channels assessed by AAS compare well with those obtained using the (86)Rb(+) efflux assay, and support the utility of nonradioactive efflux format for higher throughput screening campaigns for novel K(+) channel modulators.

01 Jan 2000·Journal of Membrane BiologyQ4 · BIOLOGY

Effects of NS1608 on MaxiK Channels in Smooth Muscle Cells from Urinary Bladder

Q4 · BIOLOGY

Article

Author: D. Newgreen ; S. Grissmer ; C. Siemer ; M. Bushfield

Using the patch-clamp technique, we have characterized membrane currents in single detrusor smooth muscle cells from rat and human urinary bladder. From the voltage- and Ca(2+)-dependence of the current as well as the single channel conductance we conclude that rat and human urinary bladder smooth muscle cells express MaxiK channels. In smooth muscle cells from rat urinary bladder we tested the action of NS1608 on current through these MaxiK channels. Application of 10 microm NS1608 increased the amplitude of the current and this increase could be explained by a shift in the activation voltage of the MaxiK channels approximately 100 mV towards more negative potentials. Charybdotoxin as well as paxilline, well known blockers of MaxiK channels, were able to reduce current through MaxiK channels in our cell preparation. In addition, application of 10 microm NS1608 hyperpolarized the membrane potential of the investigated cells. This hyperpolarization could be antagonized by the application of paxilline. We conclude that application of NS1608 results in the opening of MaxiK channels under physiological conditions that leads to a hyperpolarization of the cells. This hyperpolarization in turn could relax urinary bladder smooth muscle cells. MaxiK channels in these cells could therefore play a role in directly controlling muscle tone by regulating the membrane potential. This opens up the possibility of MaxiK channels being targets for the treatment of urge incontinence.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronary Disease	Preclinical	US	Ciba-Geigy Corp.	27 Dec 1995

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