Sawdy R, Knock G A, Bennett P R, Poston L, Aaronson P I
Department of Obstetrics and Gynaecology, Imperial College School of Medicine, Queen Charlotte's & Chelsea Hospital.
Br J Pharmacol. 1998 Nov;125(6):1212-7. doi: 10.1038/sj.bjp.0702211.
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 Ca2+ 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). Nimesulide and indomethacin caused almost complete inhibition of spontaneous myometrial contractions at concentrations of 100 and 300 microM, respectively. The Ca2+ channel current was inhibited in a concentration-dependent manner by both drugs, with a 40% reduction of the current at 100 microM nimesulide and 300 microM indomethacin. Nimesulide also accelerated the decay of the Ca2+ channel current. The inhibition of the Ca2+ channel current by 100 microM nimesulide and 300 microM indomethacin was unaffected by the presence of either PGF2alpha or PGE2 (30 microM), and was of similar magnitude whether 10 mM Ba2+ or 1.5 mM Ca2+ was used as the charge carrier. 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 Ca2+ current may contribute to this effect.
非甾体抗炎药吲哚美辛可抑制环氧化酶的组成型和诱导型形式（分别为COX-1和COX-2），而尼美舒利是一种选择性COX-2抑制剂。足月和早产前后子宫COX-2上调，前列腺素在分娩中起关键作用。因此，我们评估了这些药物对取自足月（未临产）剖宫产妇女知情同意的子宫肌层活检组织条和分离的人子宫肌层平滑肌细胞（HMSMC）的子宫肌层收缩力和电压门控Ca2+通道电流的影响。尼美舒利和吲哚美辛分别在100和300微摩尔浓度时几乎完全抑制子宫肌层的自发收缩。两种药物均以浓度依赖性方式抑制Ca2+通道电流，在100微摩尔尼美舒利和300微摩尔吲哚美辛时电流降低40%。尼美舒利还加速了Ca2+通道电流的衰减。100微摩尔尼美舒利和300微摩尔吲哚美辛对Ca2+通道电流的抑制不受PGF2α或PGE2（30微摩尔）存在的影响，并且无论使用10毫摩尔Ba2+还是1.5毫摩尔Ca2+作为载流子，抑制程度相似。抑制人妊娠子宫肌层自发收缩所需的吲哚美辛和尼美舒利浓度远高于抑制前列腺素产生所需的浓度。结果表明，尼美舒利和吲哚美辛均通过独立于环氧化酶抑制的机制抑制子宫肌层收缩力。Ca2+电流的阻断可能促成了这种效应。
