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 that were antagonized by atosiban (1 microM) and relaxed by addition of the nitric oxide donor S-nitroso L-cysteine (Cys-NO). In near-term labouring myometrium, 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 (IC(50)=1 microM) was unaffected by prior addition of the guanylyl cyclase (GC) inhibitors ODQ (1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one; 1 microM), or methylene blue (MB; 10 microM). 3. Elevation of intracellular cyclic GMP accompanying 30 microM 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 shifted the Cys-NO inhibition curve to the right and reduced the degree of relaxation produced by maximal Cys-NO treatment (100 microM in non-labouring tissue; in labouring tissue, KalTx prevented Cys-NO mediated relaxation in both stimulated 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-morpholinosyndonimine (SIN-1) did not. The failure of SIN-1 to relax OT-induced contractions 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 action. Effects of K(+)-channel inhibitors suggests that NO-induced relaxation in human uterine smooth muscle may be subserved by direct or indirect activation of one or more calcium-activated K(+)-channels.
Buxton
I L
IL
Department of Pharmacology, MS318, University of Nevada School of Medicine, Reno, NV 89557, USA. buxton@med.unr.edu
Kaiser
R A
RA
Malmquist
N A
NA
Tichenor
S
S
D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007743:Labor, Obstetric / Q000187:drug effects* / Q000502:physiology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011247:Pregnancy; D011810:Quinoxalines / Q000494:pharmacology; D026403:S-Nitrosothiols; D012604:Scorpion Venoms / Q000494:pharmacology; D013997:Time Factors; D014599:Uterus / Q000187:drug effects / Q000502:physiology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D010455:Peptides; D011810:Quinoxalines; D026403:S-Nitrosothiols; C110881:S-nitro-N-acetylpenicillamine; D012604:Scorpion Venoms; C072276:kaliotoxin; D018999:Charybdotoxin; D009569:Nitric Oxide; D010121:Oxytocin; C002385:linsidomine; C064719:iberiotoxin; C021315:S-nitrosocysteine; D008981:Molsidomine; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D003545:Cysteine