Calcium antagonistic properties of the cyclooxygenase-2 inhibitor nimesulide in human myometrial myocytes

1 The non-steroidal anti-inflammatory drug nimesulide is a selective inhibi tor of cyclooxygenase-2 which relaxes spontaneously contracting human myome trium in vivo and is potentially a useful tocolytic drug. Part of the relax ant 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). 2 Both L- and T-components of the whole cell Ca2+ channel current were inhi bited by 100 mu M nimesulide (38+/-3 and 35+/-1% block, respectively). At p hysiological pH inside and outside the cell (pH(o)/pH(i) = 7.4/7.2), this b lock did not depend on the holding or test potential, although a degree of use-dependence was observed during high frequency stimulation at a higher c oncentration of drug (300 mu M). 3 At pH(o)/pH(i) = 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 mu M, P<0.01) compared to physiological pH. Nimesulide caused a 7 mV leftward shi ft 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 hi gher than its affinity for the closed channel. We speculate that acidificat ion and depolarization of the myometrium during the intense and prolonged c ontractions of labour might increase the potency of nimesulide as a Ca2+ ch annel antagonist, promoting its action as a tocolytic agent.