NITRIC-OXIDE REGULATION OF MONKEY MYOMETRIAL CONTRACTILITY

1 We evaluated the effect of the nitric oxide (NO) donor CysNO (S-nitr oso-L-cysteine) and endogenous NO upon spontaneous contractility in no n-pregnant cynomolgus monkeys. We also assessed the role of intracellu lar guanosine 3'.5'-cyclic monophosphate ([cyclic GMP](i)) as a second messenger for NO in monkey uterine smooth muscle. 2 CysNO reduced spo ntaneous 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; CysN O inhibited contractile activity despite the complete inhibition of gu anylyl cyclase by methylene blue or LY83,583. 3 Analogues of cyclic GM P had no significant effect upon spontaneous contractile activity. L-a rginine produced a 62% reduction in spontaneous activity (P<0.05) whil e D-arginine had no effect. The competitive nitric oxide synthase (NOS ) inhibitor N-omega-nitro-L-arginine (L-NOARG) not only blocked L-argi nine-induced relaxations, but also significantly increased spontaneous contractile activity when added alone (P<0.05); the inactive D-enanti omer of NOARG had no such effect. 4 While both endogenous NO and the N O donor CysNO relax monkey myometrium, this effect is not causally rel ated to CysNO-induced elevations in [cyclic GMP](i). The failure of cy clic 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 con tractile activity seen in the presence of NOS inhibitors suggest a rol e for NO in the moment-to-moment regulation of contractile activity in this organ.