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 pharmacologic manipulation of cyclic nucleotide levels on the uterine spontaneous 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 were placed in organ chambers for isometric tension recording. Concentration-response curves were obtained for phosphodiesterase and guanylate cyclase inhibitors, membrane-permeable cyclic nucleotide analogs, and forskolin. In addition, the effects of minimal inhibitory concentrations of these agents on 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 midgestation and zaprinast induced less. Inhibitors of guanylate cyclase and membrane-permeable analogs of cyclic guanosine monophosphate were equally effective in tissues from pregnant rats at midgestation and term. All agents attenuated 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 nonselective inhibitors of phosphodiesterase, as well as membrane-permeable analogs of cyclic adenosine monophosphate, may counteract refractoriness to nitric oxide at term.

Adenylate cyclase and potassium channels are involved in forskolin- and 1,9-dideoxyforskolin-induced inhibition of pregnant rat uterus contractility.

OBJECTIVE: We sought to study the contribution of potassium channels in the effect of forskolin and 1,9-dideoxyforskolin on uterine contractility in the pregnant rat. STUDY DESIGN: Rings taken from the middle portions of uterine horns from rats at 16 days of gestation were positioned in organ chambers containing physiologic salt solution bubbled with 5% carbon dioxide in air (37 degrees C, pH approximately 7.4) for isometric tension recording under 2 g passive tension. The effects of cumulative concentrations of forskolin and 1,9-dideoxyforskolin in the absence or presence of an adenylate cyclase inhibitor (MDL-12,330A, 10(-5) mol/L), a nonselective potassium channel blocker (tetrabutylammonium, 10(-4) mol/L), or an adenosine triphosphate-dependent potassium channel blocker (glibenclamide 10(-5) mol/L) were studied. RESULTS: Both forskolin and, to a lesser extent, 1,9-dideoxyforskolin inhibit uterine contractions. Tetrabutylammonium, glibenclamide, and MDL-12, 330A attenuated the effects of forskolin, whereas glibenclamide was less effective against 1,9-dideoxyforskolin. CONCLUSION: Activation of adenylate cyclases, as well as adenosine triphosphate-dependent potassium channels and, to a greater extent, calcium-dependent potassium channels, is involved in the inhibitory effect of forskolin in uterine rings from rats at 16 days of gestation. Inhibition of uterine contractions by 1,9-dideoxyforskolin is less than that by forskolin and involves activation of adenylate cyclase and calcium-dependent potassium channels. Whether activation of guanylate cyclase is involved in the effect of the agents on calcium-dependent potassium channels needs further investigation. 1, 9-Dideoxyforskolin is not an inactive isomer of forskolin in rat uterine rings.

The effects of nitric oxide on the contractility of isolated uterine and aortic rings from pregnant rats.

OBJECTIVE: The object was to compare the effects of nitric oxide on isolated uterus and aorta of pregnant rats. STUDY DESIGN: Rings of uterus and thoracic aorta without endothelium from Sprague-Dawley rats at mid and late gestation were used for isometric tension recording. The concentration-response curve for diethylamine/nitric oxide was studied in the presence or absence of oxyhemoglobin (10(-5) mol/L), or oxyhemoglobin was added after the response to diethylamine/nitric oxide. RESULTS: Diethylamine/nitric oxide concentration dependently inhibited uterine contractions, and the effect was attenuated by previous treatment with oxyhemoglobin at mid gestation (n = 8). The effects were negligible at late gestation (n = 8). The relaxation of aortic rings by diethylamine/nitric oxide and its attenuation by previous treatment with oxyhemoglobin were similar at mid (n = 6) and late (n = 6) gestation. The sensitivity of aortic rings to diethylamine/nitric oxide is significantly higher than that of uterine rings. Oxyhemoglobin partly restored inhibited diethylamine/nitric oxide phenylephrine tension in aortic rings and had no effect on diethylamine/nitric oxide-inhibited uterine rings. CONCLUSIONS: Uterine smooth muscle is less sensitive to nitric oxide than is aortic smooth muscle. Nitric oxide sensitivity of rat uterus but not aorta decreases toward term.

Both soluble guanylate cyclase and particulate guanylate cyclase regulate myometrial contractility.

OBJECTIVE: Our purpose was to compare the effects of agents stimulating particulate and soluble guanylate cyclase with spontaneous rat uterine contractions at midgestation and term. STUDY DESIGN: Uterine rings from midgestation (day 13) and term nonlaboring (day 22) rats were positioned in organ chambers for isometric force recording. Rings were treated with increasing concentrations of atrial natriuretic peptide, permeable analogs of cyclic guanosine monophosphate, and diethylamine/nitric oxide. RESULTS: Atrial natriuretic peptide was more effective in inhibition of uterine contractions than diethylamine/nitric oxide. The 50% inhibitory concentrations were -7.4 +/- 0.12 and -7.38 +/- 0.11 for atrial natriuretic peptide and -5.68 +/- 0.09 and -4.23 +/- 0.12 for diethylamine/nitric oxide at midgestation and term, respectively. Pretreatment of uterine rings with atrial natriuretic peptide significantly attenuated inhibition of spontaneous contractions by diethylamine/nitric oxide at midgestation. CONCLUSIONS: Uterine spontaneous contractions are influenced by both soluble and particulate guanylate cyclase; the former, but not latter, is gestational age dependent.