The role of cyclic nucleotides in the spontaneous contractility and responsiveness to nitric oxide of the rat uterus at midgestation and term

OBJECTIVES: The aim of this investigation was to study the effects of pharm acologic manipulation of cyclic nucleotide levels on the uterine spontaneou s contractile activity and responsiveness to nitric oxide in pregnant rats at midgestation and term. STUDY DESIGN: Uterine rings from pregnant rats at midgestation and term wer e placed in organ chambers for isometric tension recording. Concentration-r esponse curves were obtained for phosphodiesterase and guanylate cyclase in hibitors, membrane-permeable cyclic nucleotide analogs, and forskolin. In a ddition, the effects of minimal inhibitory concentrations of these agents o n the concentration-response relationships for diethylamine nitric oxide (a nitric oxide donor) were studied. RESULTS: Nonselective phosphodiesterase inhibitors induced more inhibition of contractions of uterine rings from pregnant rats at term than at midgest ation and zaprinast induced less. Inhibitors of guanylate cyclase and membr ane-permeable analogs of cyclic guanosine monophosphate were equally effect ive in tissues from pregnant rats at midgestation and term. All agents atte nuated the inhibitory effect of diethylamine nitric oxide at midgestation; however, dibutyryl cyclic adenosine monophosphate and papaverine increased the inhibitory effect of diethylamine nitric oxide in tissues from pregnant animals at term. CONCLUSIONS: Cyclic nucleotides modulate both spontaneous and nitric oxide- induced changes in uterine contraction during pregnancy. Application of non selective inhibitors of phosphodiesterase, as well as membrane-permeable an alogs of cyclic adenosine monophosphate, may counteract refractoriness to n itric oxide at term.