Effect of nimesulide and indomethacin on contractility and the Ca 2+ channel current in myometrial smooth muscle from pregnant women

1 The non‐steroidal anti‐inflammatory drug (NSAID) indomethacin inhibits both constitutive and inducible forms of cyclo‐oxygenase (COX‐1 and COX‐2, respectively), while nimesulide is a selective COX‐2 inhibitor. Uterine COX‐2 is upregulated before and during term and pre‐term labour, and prostaglandins play a crucial role in parturition. We therefore evaluated the effects of these drugs on myometrial contractility and the voltage‐gated Ca 2+ channel current in tissue strips and isolated human myometrial smooth muscle cells (HMSMC) from myometrial biopsies taken with informed consent from women undergoing caesarean section at term (not in labour). 2 Nimesulide and indomethacin caused almost complete inhibition of spontaneous myometrial contractions at concentrations of 100 and 300 μ m , respectively. The Ca 2+ channel current was inhibited in a concentration‐dependent manner by both drugs, with a 40% reduction of the current at 100 μ m nimesulide and 300 μ m indomethacin. Nimesulide also accelerated the decay of the Ca 2+ channel current. 3 The inhibition of the Ca 2+ channel current by 100 μ m nimesulide and 300 μ m indomethacin was unaffected by the presence of either PGF 2α or PGE 2 (30 μ m ), and was of similar magnitude whether 10 m m Ba 2+ or 1.5 m m Ca 2+ was used as the charge carrier. 4 The concentrations of indomethacin and nimesulide required to suppress spontaneous contractility in human pregnant myometrium were much higher than those necessary to inhibit prostaglandin production. The results suggest that both nimesulide and indomethacin inhibit myometrial contractility via mechanisms independent of cyclo‐oxygenase inhibition. Blockade of the Ca 2+ current may contribute to this effect.British Journal of Pharmacology (1998) 125 , 1212–1217; doi: 10.1038/sj.bjp.0702211