The Physiological Role of Relaxin in the Pregnant Rat. II. The Influence of Relaxin on Uterine Contractile Activity*

Objective: This study aimed to investigate the physiological role of alternative calcium conduct once contractions triggered by oxytocin and PGF? in human myometrium. This conductance, supported by TRPC and TRPV channels, may provide alternative pathways to control either free intracellular and/or submembrane Ca2+ - concentrations, which in turn will modulate membrane polarization and contractile responses. Study design: Uterine biopsies were obtained from consenting women undergoing elective caesarian delivery at term without labor (N = 29). Isometric tension measurements were performed on uterine strips (n = 174). Amplitudes, frequencies and areas under the curve (AUC) of phasic contractions as well as resting tone were measured under various experimental conditions. Norgestimate, which has been shown to inhibit TRPC isoforms, was added to isolated organ baths to delineate their putative functional involvement. In order to assess the role of TRPV4 channels, rhythmic activity triggered by uterotonic drugs was determined in the absence and presence of either 1 ?M HC-067047 (TRPV4 antagonist) or 100 nM GSK1016790A (TRPV4 agonist). Addition of 50 nM iberiotoxin (IbTX) as well as of 10 ?M NS-1619 was also used to assess the involvement of GKCa channels in controlling uterine reactivity and contractility.Results: Micromolar concentrations of norgestimate consistently decreased the resting tone, frequency and maximal amplitude of oxytocin - and PGF2? - induced contractions. In contrast, the TRPV4 agonist GSK1016790A abolished the rhythmic contractions, resulting in a strong and reversible tocolytic effect. Addition of iberiotoxin (a GKCa blocker) reversed the effects of GSK1016790A, while NS1619 mimicked the rapid tocolytic effects of the TRPV4 agonist. Conclusion: Acute pharmacological inhibition of TRPC channels by norgestimate had minor effects on contractile parameters although resting - tone was lowered. In contrast, selectiveTRPV4 activation led to GKCa activation, which in turn hyperpolarized the myometrial cell membrane, inactivating Ca2+ channels and efficiently abrogated contractile activity. Collectively, these data suggest that alternative calcium conduct ance may play a physiological role in the modulation of myometrial reactivity prior to delivery. A rapid switch from phasic contractions to quiescence by this new class of tocolytics may potentially be of interest in delaying parturition in preterm labor.

Download Full-text

The Physiological Role of Relaxin in the Pregnant Rat. IV. The Influence of Relaxin on Cervical Collagen and Glycosaminoglycans*

Endocrinology ◽

10.1210/endo-118-2-471 ◽

1986 ◽

Vol 118 (2) ◽

pp. 471-479 ◽

Cited By ~ 46

Author(s):

S. J. DOWNING ◽

O. D. SHERWOOD

Keyword(s):

Physiological Role ◽

Pregnant Rat

Download Full-text

Erg K+ channels modulate contractile activity in the bovine epididymal duct

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00521.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. R895-R904 ◽

Cited By ~ 17

Author(s):

Marco Mewe ◽

Iris Wulfsen ◽

Anna M. E. Schuster ◽

Ralf Middendorff ◽

Günter Glassmeier ◽

...

Keyword(s):

Calcium Release ◽

Calcium Influx ◽

Contractile Activity ◽

Physiological Role ◽

Inhibitory Effect ◽

Isometric Tension ◽

Channel Blockers ◽

Current Increase ◽

Epididymal Duct

The expression and functional role of ether-à-go-go-related gene (erg) K+ channels were examined in the bovine epididymal duct. Sperm transit through the epididymal duct relies on spontaneous phasic contractions (SC) of the peritubular smooth muscle wall. Isometric tension studies revealed SC-enhancing effects of the erg channel blockers E-4031, dofetilide, cisapride, and haloperidol and SC-suppressing effects of the activator NS-1643. In the corpus epididymidis, EC50 values of 32 nM and 8.3 μM were determined for E-4031 and NS-1643, respectively. E-4031 was also able to elicit contraction in epithelium-denuded corpus segments, which lacked SC. In the cauda region, E-4031 and NS-1643 exerted effects on agonist-induced contraction similar to those observed in the proximal duct. Experiments with nifedipine and thapsigargin suggested that the excitatory effects of E-4031 depended mainly on external calcium influx and not on intracellular calcium release. Western blot and RT-PCR assays revealed the expression of both, erg1a and erg1b, in all duct regions. Because erg1b appears to predominate in the epididymal duct, patch-clamp experiments were performed on heterologously expressed erg1b channels to investigate the sensitivity of this splice variant to NS-1643. In contrast to its effects on erg1a, NS-1643 induced a concentration-dependent current increase mainly due to a marked leftward shift in erg1b channel activation by ∼30 mV at 10 μM, explaining the inhibitory effect of the drug on epididymal SC. In summary, these data provide strong evidence for a physiological role of erg1 channels in regulating epididymal motility patterns.

Download Full-text

Role of biologically active molecules in uterine contractile activity

Journal of obstetrics and women s diseases ◽

10.17816/jowd68121-27 ◽

2019 ◽

Vol 68 (1) ◽

pp. 21-27

Author(s):

Tatyana U. Kuzminykh ◽

Vera Yu. Borisova ◽

Igor P. Nikolayenkov ◽

Georgy R. Kozonov ◽

Gulrukhsor Kh. Tolibova

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Adhesion Molecules ◽

Connexin 43 ◽

Contractile Activity ◽

Active Phase ◽

Uterine Contractile ◽

Uterine Inertia ◽

Oxide Synthase

Hypothesis/aims of study. Myometrial relaxation and contraction require synchronous cellular interactions. At present, it has been established that the coordination of myometrial contractile activity is carried out by a conduction system constructed from gap junctions with intercellular channels. There are no clinical data on inhibiting (nitric oxide synthase) and activating (connexin-43) factors of uterine contractile activity in the myometrium during pregnancy and parturition in the published literature. This study was undertaken to measure the expression levels of nitric oxide synthase, adhesion molecules CD51, CD61, and connexin-43 in the myometrium during pregnancy and parturition; and to assess the role of inhibitory and activating factors in the development of uterine contractile activity. Study design, materials and methods. An immunohistochemical study of myometrial biopsy specimens obtained from the lower uterus segment during cesarean section was performed in eight women with a full-term physiological pregnancy, in another eight individuals in the active phase of uncomplicated parturition, and in eight patients with uterine inertia. Integrins (CD51 and CD61 proteins) were used as markers of cell adhesion. Localization and the number of intercellular contacts were assessed by measuring the expression level of connexin-43, with the intensity of oxidative processes assessed by nitric oxide synthase activity. Results. In the myometrium, in the active phase of physiological parturition, a three-fold increase in the expression of activating (CD51, CD61, and connexin-43) factors of uterine contractile activity and a five-fold decrease in that of inhibitory (nitric oxide synthase) ones occur compared to those in full-term physiological pregnancy. Conclusion. In the pathogenesis of uterine inertia and resistance to labor induction, an important role is played by the decreased expression of adhesion molecules (CD51, CD61) and connexin-43 and the increased expression of nitric oxide synthase in the myometrium.

Download Full-text

The role of potassium channels and calcium in the relaxation mechanism of magnesium sulfate on the isolated rat uterus

Archives of Biological Sciences ◽

10.2298/abs180615031s ◽

2019 ◽

Vol 71 (1) ◽

pp. 5-11 ◽

Cited By ~ 1

Author(s):

Dragana Sokolovic ◽

Dragana Drakul ◽

Zorana Orescanin-Dusic ◽

Nikola Tatalovic ◽

Milica Pecelj ◽

...

Keyword(s):

Potassium Channels ◽

Potassium Channel ◽

Contractile Activity ◽

Specific Inhibitor ◽

Relaxation Mechanism ◽

Uterine Contractile ◽

Dependent Inhibition ◽

Calcium Activated Potassium Channels ◽

Uterine Relaxation

MgSO4 is used as a tocolytic agent. It is considered to be a calcium channel antagonist, but a different mechanism of its action might be involved. The aim of this study was to examine the contribution of calcium concentrations and potassium channels in the mechanism of MgSO4-mediated uterine relaxation. Isolated uteri from female Wister rats were treated with increasing MgSO4 concentrations (0.1-30 mM). MgSO4 induced dose-dependent inhibition of spontaneous activity. Addition of Ca2+ (6 mM and 12 mM) stimulated uterine contractile activity and attenuated the inhibitory activity of MgSO4. In order to analyze the role of different subtypes of potassium channels, Ca2+-stimulated uteri were pretreated with glibenclamide (Glib), a selective ATP-sensitive potassium channel inhibitor (KATP), tetraethylammonium (TEA), a non-specific inhibitor of large conductance calcium-activated potassium channels (BKCa), and 4-aminopyridine (4-AP), a voltage-sensitive potassium channel inhibitor (Kv), at concentrations that had no effect per se. Pretreatment with 4-AP had no effect on MgSO4-mediated relaxation of Ca2+-stimulated uteri. The relaxing effect of MgSO4 was potentiated by pretreatment with glibenclamide. Pretreatment with TEA attenuated the MgSO4-mediated decrease in frequency. Our results suggest that MgSO4 acts as a general calcium antagonist that influences Ca2+-mediated potassium channels. Furthermore, it seems that MgSO4 uterine relaxation activity is partially mediated by selective ATP-sensitive potassium channels, suggesting an ATP-dependent role.

Download Full-text