Cyclic GMP‐independent effects of nitric oxide on guinea‐pig uterine contractility

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Abstract
The role of nitric oxide (NO) in the regulation of uterine contractility has yet to be clearly defined. We evaluated the effect of NO (in the form of S‐nitroso‐L‐cysteine, CysNO) upon uterine contractility and guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) accumulation in pregnant and nonpregnant guinea‐pig myometrium. While CysNO had no effect upon spontaneous contractile activity in either pregnant or nonpregnant uterine tissues, addition of CysNO resulted in an immediate and reversible relaxation of oxytocin‐ or acetylcholine (ACh)‐evoked contractions. Relaxation of agonist‐evoked contractions in response to CysNO was associated with significant elevations in intracellular cyclic GMP concentrations ([cyclic GMP]i). Elevations in [cyclic GMP]i were not required for relaxation, as inhibition of guanylyl cyclase by methylene blue prevented [cyclic GMP]i accumulation while having no effect upon the ability of CysNO to relax agonist‐evoked contractions. Addition of the cyclic GMP‐analogues, 8‐Br‐cyclic GMP and PET‐cyclic GMP, only at high concentrations, produced partial relaxation of agonist‐contracted tissues, suggesting the possibility that cyclic GMP may be sufficient but not necessary for myometrial relaxation. Our studies not only provide evidence for a functional role for NO‐modulation of agonist‐evoked contractions in the pregnant and nonpregnant guinea‐pig uterus, but also that these occur by a mechanism which is not dependent upon guanylyl cyclase activity.