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

Kuenzli, Karri A.; Bradley, Michael E.; Buxton, Martin

doi:10.1111/j.1476-5381.1996.tb15734.x

Cited by 46 publications

(37 citation statements)

References 30 publications

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“…We have examined the heretical notion that relaxation of the myometrium by NO is independent of cGMP elevation as a result of soluble guanylyl cyclase. Although this notion was initially rejected by many on the basis that the dogma established by the 1998 Nobel for Physiology or Medicine [25] demanded that NO signals through cGMP in smooth muscle, it is now clearly established from our work and that of others that NO-mediated relaxation of uterine muscle is independent of global cGMP elevation no matter whether this is studied in animal [26] , primate [27] or human [28] . Cyclic GMP is not without effect however.…”

Section: No-mediated Relaxationmentioning

confidence: 89%

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

Buxton

Heyman

et al. 2011

Acta Pharmacol Sin

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Rates of premature birth are alarming and threaten societies and healthcare systems worldwide. Premature labor results in premature birth in over 50% of cases. Preterm birth accounts for three-quarters of infant morbidity and mortality. Children that survive birth before 34 weeks gestation often face life-long disability. Current treatments for preterm labor are wanting. No treatment has been found to be generally effective and none are systematically evaluated beyond 48 h. New approaches to the treatment of preterm labor are desperately needed. Recent studies from our laboratory suggest that the uterine muscle is a unique compartment with regulation of uterine relaxation unlike that of other smooth muscles. Here we discuss recent evidence that the mechanically activated 2-pore potassium channel, TREK-1, may contribute to contraction-relaxation signaling in uterine smooth muscle and that TREK-1 gene variants associated with human labor and preterm labor may lead to a better understanding of preterm labor and its possible prevention.

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Section: No-mediated Relaxationmentioning

confidence: 89%

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

Buxton

Heyman

et al. 2011

Acta Pharmacol Sin

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“…There are conflicting reports in the literature concerning its role in the regulation of myometrial contractility. Functional studies in the rat and guinea pig reported that the myometrium is relatively insensitive to cGMP (5,7,15), especially in comparison to vascular smooth muscle (16). The other study, in contrast, demonstrated that cGMP can modulate myometrial contractile activity (8).…”

Section: Discussionmentioning

confidence: 85%

“…These studies offered evidence consistent with current dogma, that the effect of NO on uterine smooth muscle relaxation occurs via elevations in cGMP and concluded that an NO-GC relaxation pathway exists in the uterine smooth muscle. However, the other study (5) reported that NO can indeed alter agonist-evoked uterine contractility, but the effect of NO does not require the activation of cGMP. The novel NO-independent type of sGC activator YC-1 has attracted much attention recently because of its unique action profile.…”

Section: Discussionmentioning

confidence: 96%

“…They are activated by NO and peptide hormones, respectively (11,17). NO is clearly an effective agent in relaxing spontaneous contractions in both animal (5,6,10,18) and human myometrium (7,9,18,19). Despite the number of morphological and biochemical analyses evaluating the presence of the enzyme necessary to produce NO in the uterus, only a few investigators have explored the possible mechanism of NO in the uterus (9,10,18).…”

Section: Discussionmentioning

confidence: 99%

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YC-1, a Nitric Oxide-Independent Activator of Soluble Guanylate Cyclase, Inhibits the Spontaneous Contractions of Isolated Pregnant Rat Myometrium

et al. 2004

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Abstract. The aim of this study was to investigate the effect of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole) on spontaneous contractions and levels of cyclic GMP (cGMP) of myometrial strips isolated from pregnant rats. It is a nitric oxide-independent soluble guanylate cyclase activator. Myometrial strips were obtained from eight pregnant Wistar albino rats and were mounted in organ baths for the recording of isometric tensions. We evaluated the effect of increasing concentrations of YC-1 on spontaneous myometrial contractions and on contractions of myometrial smooth muscle pretreated with methylene blue (10 -5 M), tetraethylammonium chloride (TEA) (3´10 -4 M), and glibenclamide (10 -6 M). YC-1 (10 -9 -3´10 -5 M) concentration-dependently decreased the amplitude and frequency of spontaneous contractions of myometrial strips. The inhibition of the amplitude and frequency of spontaneous contractions by YC-1 were antagonized with methylene blue (10 -5 M) and TEA (3´10 -4 M), but they were not changed by glibenclamide (10 -6 M); however, the antagonistic effect of methylene blue was significantly more than that of TEA (P<0.05). We also evaluated the effect of YC-1 on the levels of cGMP in myometrial strips obtained from pregnant rat uterine horns. YC-1-stimulated myometrial strips showed an excessive elevation in myometrial cGMP that declined slowly during the subsequent washout period. These results show that YC-1 decreases spontaneous contractile activity of myometrial strips isolated from pregnant rat and causes elevation of myometrial cGMP levels in vivo. This effect of YC-1 is significantly reduced by the methylene blue and TEA, suggesting the activation of soluble guanylate cyclase and Ca 2+-sensitive K + channels as the mechanisms of action.

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“…The IC 50 for the transnitrosylating agent cysteine-NO to relax human myometrium in tissue bath experiments is approximately 1 M (Buxton et al, 2001). Elevations in cGMP that accompany NO stimulation can be prevented by pretreatment of tissues with inhibitors of soluble guanylyl cyclase such as 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (Buxton et al, 2001), 6-anilino-5,8-quinolinedione (LY 83583), (Kuenzli et al, 1998), or 3,7-bis(dimethylamino) phenothiazin-5-ium (methylene blue), (Kuenzli et al, 1996). Stimulation of 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one-treated myometrial tissues with NO donors results in relaxation without cGMP elevation.…”

Section: Introductionmentioning

confidence: 99%

Uterine Smooth Muscle S-Nitrosylproteome in Pregnancy

Ulrich¹,

Quillici²,

Schegg³

et al. 2012

Molecular Pharmacology

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The molecular mechanisms involved in uterine quiescence during gestation and those responsible for induction of labor are not completely known. Nitric oxide relaxes uterine smooth muscle in a manner disparate from that for other smooth muscles because global elevation of cGMP after activation of soluble guanylyl cyclase does not relax the muscle. S-Nitrosylation, the covalent addition of an nitric oxide (NO) group to a cysteine thiol is a likely mechanism to explain the ability of NO to relax myometrium. This work is the first to describe the myometrial S-nitrosylproteome in both pregnant and nonpregnant tissue states. Using the guinea pig model, we show that specific sets of proteins involved in contraction and relaxation are S-nitrosylated in laboring and nonlaboring muscle and that many of these proteins are uniquely S-nitrosylated in only one state of the tissue. In particular, we show that S-nitrosylation of the intermediate filament protein desmin is significantly increased (5.7-fold, p Ͻ 0.005) in pregnancy and that this increase cannot be attributed solely to the increase in protein expression (1.8-fold, p Ͻ 0.005) that accompanies pregnancy. Elucidation of the myometrial S-nitrosylproteome provides a list of mechanistically important proteins that can constitute the basis of hypotheses formed to explain the regulation of uterine contraction/relaxation.

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

Cited by 46 publications

References 30 publications

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

YC-1, a Nitric Oxide-Independent Activator of Soluble Guanylate Cyclase, Inhibits the Spontaneous Contractions of Isolated Pregnant Rat Myometrium

Uterine Smooth Muscle S-Nitrosylproteome in Pregnancy

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