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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Knock, G. A. Aaronson, P. I. |
| Description | Author Affiliation: Knock GA ( London Myometrial Group and Division of Pharmacology and Therapeutics, King's College London.) |
| Abstract | The non-steroidal anti-inflammatory drug nimesulide is a selective inhibitor of cyclooxygenase-2 which relaxes spontaneously contracting human myometrium in vivo and is potentially a useful tocolytic drug. Part of the relaxant action of nimesulide may be via block of myometrial Ca2+ channels. Here, we describe the Ca2+ channel blocking properties of nimesulide in freshly dispersed human term-pregnant myometrial smooth muscle cells (HMSMCs). Both L- and T-components of the whole cell Ca2+ channel current were inhibited by 100 microM nimesulide (38+/-3 and 35+/-1% block, respectively). At physiological pH inside and outside the cell (pHo/pHi = 7.4/7.2), this block did not depend on the holding or test potential, although a degree of use-dependence was observed during high frequency stimulation at a higher concentration of drug (300 microM). At pHo/pHi = 6.8, under which condition the concentration of the non-ionized form of the drug is increased 3 fold compared to pH 7.4, nimesulide blocked the L-type current more potently (58+/-3% inhibition at 100 microM, P<0.01) compared to physiological pH. Nimesulide caused a 7 mV leftward shift in the availability curve of the current at pH 6.8, suggesting that the affinity of the drug for the inactivated channel is approximately 4 fold higher than its affinity for the closed channel. We speculate that acidification and depolarization of the myometrium during the intense and prolonged contractions of labour might increase the potency of nimesulide as a Ca2+ channel antagonist, promoting its action as a tocolytic agent. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 6 |
| Volume Number | 127 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 1999-07-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Calcium Channel Blockers Pharmacology Cyclooxygenase Inhibitors Isoenzymes Drug Effects Myometrium Prostaglandin-Endoperoxide Synthases Sulfonamides Calcium Channels Physiology Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Dose-Response Relationship, Drug Electric Stimulation Hydrogen-Ion Concentration Kinetics Membrane Potentials Membrane Proteins Cytology Enzymology Patch-Clamp Techniques Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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