The inhibitory concentration of atrial natriuretic factor at
The 50% inhibitory concentration of atrial natriuretic factor at midgestation and term are –7.4 ± 0.12 and –7.38 ± 0.11, respectively, demonstrating no gestational age dependency in the effect of atrial natriuretic factor on spontaneous contractile activity.
Diethyl amine/nitric oxide starts to inhibit spontaneous uterine contractions at a concentration of 10–6 mol/L at both midgestation and term (Fig 1). The maximal inhibition of the contractions is more pronounced at midgestation (around 80% of basal activity) compared with term. The 50% inhibitory concentrations of diethyl amine/nitric oxide are –5.68 ± 0.09 and –4.23 ± 0.12 at midgestation and term, respectively. Inhibition of spontaneous contraction of rat nkcc inhibitor induced by membrane-permeable cyclic guanylate monophosphate analogs does not demonstrate gestational age dependency (Fig 2).
The 50% inhibitory concentration values for dibutyryl cyclic guanylate monophosphate are –4.68 ± 0.13 and –4.55 ± 0.12 at midgestation and term, respectively, and for 8-bromo cyclic guanylate monophosphate, they are –4.88 ± 0.11 and –4.78 ± 0.13 at midgestation and term, respectively.
Preincubation of uterine rings with a 50% inhibitory concentration of atrial natriuretic factor (3 × 10–8 mol/L) attenuates the inhibition of spontaneous contractions induced by diethyl amine/nitric oxide at midgestation (Fig 3, A).
The 50% inhibitory concentrations of diethyl amine/nitric oxide are –5.68 ± 0.09 and –5.1 ± 0.15 (P < .05) in the absence and presence of atrial natriuretic factor, respectively. In the uterine rings from term pregnant rats atrial natriuretic factor does not significantly affect the inhibition of spontaneous uterine contractions induced by diethyl amine/nitric oxide (). The 50% inhibitory concentrations of diethyl amine/nitric oxide are –4.23 ± 0.12 and –4.26 ± 0.12 in the absence and presence of atrial natriuretic factor, respectively.
Comment Atrial natriuretic factor and nitrovasodilators increase the intracellular level of cyclic guanylate monophosphate, thus inducing relaxation of vascular smooth muscle. Although atrial natriuretic factor and nitric oxide act by different forms of guanylate cyclase,2, 3, 4 the end result is the same—an increase in intracellular levels of cyclic guanylate monophosphate leading to a decrease in cytosolic Ca++ levels. In this study atrial natriuretic factor starts to inhibit rat uterine contractions at a concentration of 10–8 mol/L. At the final concentration of 10–7 mol/L, atrial natriuretic factor caused 40% inhibition. We realize that more inhibition would be expected at higher concentrations of atrial natriuretic factor, and the presented 50% inhibitory concentrations do not reflect the true 50% inhibitory concentration of atrial natriuretic factor that may be obtained with the full concentration range of atrial natriuretic factor. In other studies rat uterine longitudinal strips were shown to be refractory to inhibitory effects of atrial natriuretic factor, nitric oxide donors, and a cyclic guanylate monophosphate analog at the time of delivery. The absence of refractoriness to atrial natriuretic factor inhibition of spontaneous contractions in this study may be due to the following: (1) We used increasing concentrations instead of a single concentration; (2) rings of uteri instead of longitudinal strips were used in the study. Nitric oxide donor refractoriness at term seen in this study was similar to that seen in previous studies.8, 9, 10 The refractoriness to a cyclic guanylate monophosphate analog seen at the time of delivery, shown as a shift of concentration-response curves to the right, indicates a decrease in the sensitivity to the agent. However, the maximal inhibitory effects were similar to pregnant uterine strips. In this study we did not see the change in sensitivity or in the maximal inhibition in term, nondelivering rat uterine rings. Activation of particulate and soluble guanylate cyclases results in equal relaxation in tracheal and vessel preparations.3, 4 However, the higher quantity and increased expression of particulate guanylate cyclase receptors noted in myometrium in pregnancy11, 12, 13 may explain the effect of atrial natriuretic factor observed in this study. Atrial natriuretic factor receptors and their expression in the myometrium at different stages of gestation need to be analyzed further for a better understanding of the role of particulate guanylate cyclase in the regulation of uterine contractility.