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.