Nitric oxide relaxes human myometrium by a cGMP-independent mechanism.
The role of intracellular guanosine 3',5'-cyclic monophosphate concentration ([cGMP]i) in nitric oxide (NO)-mediated relaxations in the uterus has become controversial. We found the NO donor S-nitroso-L-cysteine (CysNO) to potently (IC50 = 30 nM) inhibit spontaneous contractions in the nonpregnant human myometrium. CysNO treatment increased [cGMP]i significantly (P < 0.001), and this increase was blocked by the guanylyl cyclase inhibitors methylene blue (10 microM) or LY-83583 (1 microM); however, pretreatment with these guanylyl cyclase inhibitors failed to block CysNO-mediated relaxations. Intracellular cAMP concentrations were not altered by treatment of tissues with 10 microM CysNO. Incubation with the cGMP analogs 8-bromo-cGMP or beta-phenyl-1,N2-etheno-cGMP did not significantly affect spontaneous contractility. Pretreatment of tissues with charybdotoxin [a calcium-dependent potassium channel (BK) blocker] completely reversed CysNO-induced relaxations. We conclude that NO is a potent inhibitor of spontaneous contractile activity in the nonpregnant human uterus and that, although guanylyl cyclase and BK activities are increased by NO, increases in [cGMP]i are not required for NO-induced relaxations in this tissue.
Bradley
K K
KK
Department of Pharmacology, University of Nevada, Reno, Nevada 89557, USA.
Buxton
I L
IL
Barber
J E
JE
McGaw
T
T
Bradley
M E
ME
D000634:Aminoquinolines / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D008751:Methylene Blue / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D026403:S-Nitrosothiols; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D018999:Charybdotoxin; D009569:Nitric Oxide; C041715:6-anilino-5,8-quinolinedione; C021315:S-nitrosocysteine; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D003545:Cysteine; D008751:Methylene Blue