NO-induced relaxation of labouring and non-labouring human myometrium is not mediated by cyclic GMP

1 In myometrial strips from near-term non-labouring human uterus, addition of oxytocin (OT) evoked dose-dependent (10 - 3000 nM) phasic contractions t hat were antagonized by atosiban (1 muM) and relaxed by addition of the nit ric oxide donor S-nitroso L-cysteine (Cys-NO). In near-term labouring myome trium, however, addition of OT was ineffective at raising additional tone. 2 In both labouring and non-labouring tissue, Cys-NO mediated relaxation of spontaneous or OT-induced contractions (IC50 = 1 muM) was unaffected by pr ior addition of the guanylyl cyclase (GC) inhibitors ODQ (1H-[1,2,4]oxadiaz olo[4,3,-alpha ]quinoxalin-1-one; 1 muM), or methylene blue (MB; 10 muM). 3 Elevation of intracellular cyclic GMP accompanying 30 muM Cys-NO addition in non-labouring tissue (7.5 fold) or in labouring tissues (2.5 fold) was completely blocked in tissues that had been pre-treated with ODQ or MB. 4 Charybdotoxin (ChTx), iberiotoxin (IbTx) and kaliotoxin (KalTx) all shift ed the Cys-NO inhibition curve to the right and reduced the degree of relax ation produced by maximal Cys-NO treatment (100 muM in non-labouring tissue ; in labouring tissue, KalTx prevented Cys-NO mediated relaxation in both s timulated and unstimulated tissue. 5 Addition of the NO-donor S-nitroso N-acetyl penicillamine (SNAP) produced a dose-dependent relaxation of pregnant myometrium while 3-morpholinosyndo nimine (SIN-1) did not. The failure of SIN-1 to relax OT-induced contractio ns was not due to a failure of the donor to stimulate myometrial GC. 6 We demonstrate that despite the ability of NO to stimulate myometrial GC in pregnant uterine muscle, relaxations are independent of cyclic GMP actio n. Effects of K+-channel inhibitors suggests that NO-induced relaxation in human uterine smooth muscle may be subserved by direct or indirect activati on of one or more calcium-activated K+-channels.