Nitric oxide regulation of monkey myometrial contractility.
1. We evaluated the effect of the nitric oxide (NO) donor CysNO (S-nitroso-L-cysteine) and endogenous NO upon spontaneous contractility in non-pregnant cynomolgus monkeys. We also assessed the role of intracellular guanosine 3',5'-cyclic monophosphate ([cyclic GMP]i) as a second messenger for NO in monkey uterine smooth muscle. 2. CysNO reduced spontaneous contractility by 84% (P < 0.05) at maximal concentrations, and significantly elevated [cyclic GMP]i (P < 0.05). However, increases in [cyclic GMP]i were not required for CysNO-induced relaxations; CysNO inhibited contractile activity despite the complete inhibition of guanylyl cyclase by methylene blue or LY83,583. 3. Analogues of cyclic GMP had no significant effect upon spontaneous contractile activity. L-arginine produced a 62% reduction in spontaneous activity (P < 0.05) while D-arginine had no effect. The competitive nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NOARG) not only blocked L-arginine-induced relaxations, but also significantly increased spontaneous contractile activity when added alone (P < 0.05); the inactive D-enantiomer of NOARG had no such effect. 4. While both endogenous NO and the NO donor CysNO relax monkey myometrium, this effect is not causally related to CysNO-induced elevations in [cyclic GMP]i. The failure of cyclic GMP analogues to alter monkey uterine smooth muscle tension also argues against a role for [cyclic GMP]i in the regulation of uterine contractility. Not only do these findings argue for the existence of a functionally-relevant NOS in the monkey uterus, but increases in contractile activity seen in the presence of NOS inhibitors suggest a role for NO in the moment-to-moment regulation of contractile activity in this organ.
Kuenzli
K A
KA
Department of Pharmacology, University of Nevada, Reno 89577-0046, USA.
Buxton
I L
IL
Bradley
M E
ME
D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D026403:S-Nitrosothiols; D013379:Substrate Specificity; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D004791:Enzyme Inhibitors; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D003545:Cysteine