Effects of cGMP and the nitric oxide donors glyceryl trinitrate and sodium nitroprusside on contractions in vitro of isolated myometrial tissue from pregnant women

Abstract

The purpose of this study was to determine the relaxant effects in vitro of two nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, which are currently available for use in vivo, on contractions of non-labouring myometrium from pregnant women. Since nitric oxide also mediates relaxation by increasing the concentration of cGMP, sensitivity to 8-bromo-cGMP (a cGMP analogue) was also determined. The effects of the K(+)-channel opener lemakalim and of the Ca(2+)-channel blocker nifedipine were studied for comparison. After the addition of glyceryl trinitrate (0.1-100 mumol l-1), sodium nitroprusside (0.1-100 mumol l-1) or 8-bromo-cGMP (0.001-3 mmol l-1), the spontaneous rhythmic contractility of myometrial strips was inhibited in a concentration-dependent manner: the maximum inhibition produced by the highest tested concentration of each drug was 40 +/- 7%, 53 +/- 8% and 39 +/- 8% of the original degree of contraction, respectively. Myometrial contractions were completely abolished by lemakalim and by nifedipine and verapamil at concentrations of > or = 10(-5) mol l-1. The nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, attenuate myometrial contractions and are therefore useful as tocolytic agents. However, at equimolar concentrations in vitro, the ability of glyceryl trinitrate and sodium nitroprusside to attenuate myometrial contractions is less than that of lemakalin, nifedipine and verapamil. Controlled trials are required to determine the side-effects and clinical efficacy of each of these agents in vivo.

Cervical maturation and labor induction

“…11,12) The involvement of NO as a major actor of cervical ripening would be consistent with the fact that cervical softening occurs during pregnancy, far before uterine contractions. This may also explain why cervical ripening induced by anti-progesterone is not prevented by COX-inhibitors.…”

Transdermal Nitroglycerin Versus Oral Nifedipine for Suppression of Preterm Labor

“…GTN, a nitric oxide donor, has been shown to produce a significant decrease in the contractility of human myometrium in pregnant and non-pregnant women in vitro (7)(8)(9)(10). In 1994, Lees et al (11) reported that transdermal nitroglycerin patches suppressed uterine contractions in all 20 episodes of preterm labor that occurred in 13 consecutive women enrolled in a pilot study, and they hence suggested that this nitric oxide donor could be an effective and safe tocolytic agent.…”

Molecular mechanism of cGMP-mediated smooth muscle relaxation

“…These agents stimulate the endothelial cell to produce and release NO, which in turn acts on the SMC to increase cGMP production. The ability of NO to relax SM has been described in multiple models and muscle types, including tracheal smooth muscle (Jia et al, 1995;Kannan and Johnson, 1995;Ward et al, 1995;Sadeghi-Hashjin et al, 1996;Yamakage et al, 1996), vascular smooth muscle (Landgraf et al, 1986;White et al, 1995;Moro et al, 1996;Olson et al, 1997), and myometrium (Buhimschi et al, 1995;Kuenzli et al, 1996;Nakanishi et al, 1996;Norman et al, 1997;Hennan and Diamond, 1998).…”