Nitric oxide regulation of monkey myometrial contractility

Abstract

1 We evaluated the e ect 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% (P50.05) at maximal concentrations, and signi®cantly elevated [cyclic GMP] i (P50.05). 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 signi®cant e ect upon spontaneous contractile activity. L-arginine produced a 62% reduction in spontaneous activity (P50.05) while D-arginine had no e ect. The competitive nitric oxide synthase (NOS) inhibitor N o -nitro-L-arginine (L-NOARG) not only blocked Larginine-induced relaxations, but also signi®cantly increased spontaneous contractile activity when added alone (P50.05); the inactive D-enantiomer of NOARG had no such e ect. 4 While both endogenous NO and the NO donor CysNO relax monkey myometrium, this e ect 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 ®ndings 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.

Mechanical activity of frog esophagus muscle in response to electrical stimulation of intramural nerves

“…These results suggest that the relaxation response is produced by NANC inhibitory nerve excitation. NANC inhibitory nerves have been reported to be present in the guinea-pig caecum (Burnstock et al, 1966), the dog stomach (Ohga et al, 1970), the opossum esophageal sphincter (Daniel et al, 1989), the human uterus (Jones et al, 1997) and the monkey uterus (Kuenzli et al, 1998). The present experiments have demonstrated that functional NANC inhibitory nerves are distributed in the frog esophagus.…”

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

“…We have examined the heretical notion that relaxation of the myometrium by NO is independent of cGMP elevation as a result of soluble guanylyl cyclase. Although this notion was initially rejected by many on the basis that the dogma established by the 1998 Nobel for Physiology or Medicine [25] demanded that NO signals through cGMP in smooth muscle, it is now clearly established from our work and that of others that NO-mediated relaxation of uterine muscle is independent of global cGMP elevation no matter whether this is studied in animal [26] , primate [27] or human [28] . Cyclic GMP is not without effect however.…”

YC-1, a Nitric Oxide-Independent Activator of Soluble Guanylate Cyclase, Inhibits the Spontaneous Contractions of Isolated Pregnant Rat Myometrium

“…They are activated by NO and peptide hormones, respectively (11,17). NO is clearly an effective agent in relaxing spontaneous contractions in both animal (5,6,10,18) and human myometrium (7,9,18,19). Despite the number of morphological and biochemical analyses evaluating the presence of the enzyme necessary to produce NO in the uterus, only a few investigators have explored the possible mechanism of NO in the uterus (9,10,18).…”