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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Mchale, N. G. Thornbury, K. D. Webb, T. I. Large, R. J. Hollywood, M. A. Sergeant, G. P. Bradley, E. Roy, S. Akande, A. Kshatri, A. |
| Description | Author Affiliation: Large RJ ( The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co. Louth, Ireland.) |
| Abstract | BACKGROUND AND PURPOSE: GoSlo-SR compounds are efficacious BK (KCa 1.1) channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. EXPERIMENTAL APPROACH: A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BK alone or in combination with either ß1 or ß4 subunits. KEY RESULTS: GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2 ) of BK channels approximately -100 mV, irrespective of the presence of regulatory ß subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by approximately -100 mV; however, this was reduced by â ¼80% in HEK cells expressing only BK subunits. When ß1 or ß4 subunits were co-expressed with BK , efficacy was restored. GoSlo-SR-5-130 caused a concentration-dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels. CONCLUSIONS AND IMPLICATIONS: GoSlo-SR-5-130 required ß1 or ß4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of ß subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. The novel BK channel opener, GoSlo-SR-5-130, is approximately fivefold more efficacious on BK channels with regulatory ß subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 10 |
| Volume Number | 172 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2015-05-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Anthraquinones Pharmacology Large-Conductance Calcium-Activated Potassium Channel Beta Subunits Physiology Protein Subunits Sulfonic Acids Animals Cells, Cultured HEK293 Cells Large-Conductance Calcium-Activated Potassium Channel Alpha Subunits Agonists Membrane Potentials Drug Effects Muscle Contraction Muscle, Smooth Genetics Rabbits Transfection Urinary Bladder Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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