Investigating the effects of the Rho-kinase enzyme inhibitors AS1892802 and fasudil hydrochloride on the contractions of isolated pregnant rat myometrium

Ergül, Mustafa; Turgut, Nergiz Hacer; Saraç, Bülent; Altun, Ahmet; Yıldırım, Seda; Bağcıvan, İhsan

doi:10.1016/j.ejogrb.2016.04.031

Cited by 7 publications

(3 citation statements)

References 35 publications

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“…In rabbits, myometrial RhoA and ROCK1 expression is significantly higher in late pregnant animals, a finding that is accompanied by increased calcium sensitivity [30]. In vitro inhibition of the RhoA pathway in myometrial strips of term pregnant rats diminished the amplitude and frequency of oxytocin induced contractions [29,31], and a potent cumulative relaxant effect on oxytocin induced human myometrial contractility was also demonstrated in vitro [25].…”

Section: Introductionmentioning

confidence: 97%

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Frehner

Reichler

Kowalewski

et al. 2021

Journal of Reproduction and Development

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The underlying functional and molecular changes in canine primary uterine inertia (PUI) are still not clarified. Leptin (Lep) and obesity negatively affect uterine contractility in women, partly mediated by the RhoA/Rho kinase pathway, affecting myometrial calcium sensitization. We hypothesized that increased uterine Lep/Lep receptor (LepR) or decreased RhoA/Rho kinase expression contributes to PUI in dogs, independent of obesity. Dogs presented for dystocia were grouped into PUI (n = 11) or obstructive dystocia (OD, still showing strong labor contractions; n = 7). Interplacental full-thickness uterine biopsies were collected during Cesarean section for relative gene expression (RGE) of RhoA, its effector kinases (ROCK1, ROCK2), Lep and LepR by qPCR. Protein and/or mRNA expression was evaluated by immunohistochemistry and in situ hybridization. RGE was compared between groups by one-way ANOVA using body weight as covariate with statistical significance P < 0.05. Uterine ROCK1 and ROCK2 gene expression was significantly higher in PUI than OD, while RhoA and Lep did not differ. LepR RGE was below the detection limit in 5 PUI and all OD dogs. Litter size had no influence. Lep, LepR, RhoA, ROCK1, ROCK2 protein and/or mRNA were localized in the myometrium and endometrium. Uterine protein expression appeared similar between groups. LepR mRNA signals appeared stronger in PUI than OD. In conclusion, lasting, strong labor contractions in OD resulted in downregulation of uterine ROCK1 and ROCK2, contrasting the higher expression in PUI dogs with insufficient contractions. The Lep-LepR system may affect uterine contractility in nonobese PUI dogs in a paracrine-autocrine manner.

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Section: Introductionmentioning

confidence: 97%

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Frehner

Reichler

Kowalewski

et al. 2021

Journal of Reproduction and Development

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“…Although calcium sensitization involving Rho kinase is involved in α 1 -adrenoceptor mediated contractions in at least some tissues in the rat [ 6 , 7 ], the overall role of RhoA/Rho kinase in α 1 -adrenoceptor mediated contractions has not been established [ 8 ]. In rat aorta, contractions to both phenylephrine [ 9 ] and angiotensin II [ 10 ] involve Rho kinase.…”

Section: Introductionmentioning

confidence: 99%

Involvement of α_1B-adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen

Alsufyani

Docherty

2023

Korean J Physiol Pharmacol

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α 1 -adrenoceptors link via the G-protein Gq/G 11 to both Ca 2+ entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α 1 -adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α 1 -adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α 1 -adrenoceptor mediated as they are competitively blocked by prazosin. The α 1A -adrenoceptor antagonist RS100329 had low potency in rat aorta. The α 1D -adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α 1D -adrenoceptors and high concentrations blocking α 1B -adrenoceptors. The Rho kinase inhibitor fasudil (10 µM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α 1B -adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α 1 -adrenoceptor are involved in contractions to NA, fasudil (3 µM) significantly reduced both early and late components to the NA contraction, the early component involving α 1B - and α 1D -adrenoceptors, and the late component involving α 1B - and α 1A -adrenoceptors. This suggests that fasudil inhibits α 1B -adrenoceptor mediated responses. It is concluded that α 1D - and α 1B -adrenoceptors interact in rat aorta and α 1D -, α 1A - and α 1B -adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α 1B -adrenoceptor.

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“…62 However, in view of the diverse targets of action, the possibility of fetal malformations or demise cannot be overlooked. 63 The lack of enough data of use in humans eyes, and owing to the potential teratogenic risks, netarsudil should be avoided in pregnancy, especially the first trimester ( Table 2 ). 64 Also, its safety during breastfeeding is not clear.…”

Section: Treatment Optionsmentioning

confidence: 99%

Management of glaucoma in pregnancy – balancing safety with efficacy

et al. 2021

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Glaucoma and pregnancy is an uncommon combination, but it constitutes a very challenging situation for the treating doctor. The challenge is not only controlling the intraocular pressure and preventing glaucoma progression in the mother, but also having to deal with her mental stress and anxiety regarding the safety of her child. The situation is further worsened by the lack of definite guidelines as to how to deal with such patients. Relative rarity of glaucoma in this population restricts any large prospective randomized clinical trials or any large systematic studies. Moreover, none of the existing anti-glaucoma medications is absolutely safe in pregnancy. Current practice patterns depend on some case reports, a few observational studies and a few animal studies that attempt at determining the safety and efficacy of the available medicines. These are then prescribed on the basis of their relative safety in any particular stage of pregnancy or lactation. Newer medications that were released recently in 2018, such as Vyzulta and Rhopressa, presently have limited data to support their safety for use during pregnancy. Laser trabeculoplasty, conventional filtration surgery (of course without anti-metabolites), and minimally invasive glaucoma surgery represent a few non-pharmacological management options. Surgical procedures such as trabeculectomy and tube-shunts or collagen matrix implants, and newer minimally invasive glaucoma surgery procedures such as the gelatin stents are currently being explored and may prove to be viable solutions for severe glaucoma during pregnancy, although they too have their own inherent drawbacks. Management of glaucoma during pregnancy and lactation requires careful consideration of the disease status, gestational stage, US Food and Drug Administration classification and guidelines, and potential benefits and limitations of the various therapeutic modalities. This review focuses on the importance of a multidisciplinary team approach, starting with preconception planning and counseling, determining the treatment options depending on the stage of glaucoma and of pregnancy, and emphasizes the involvement of the patients, their obstetrician, and pediatrician through active discussion regarding the various medical, laser, or surgical modalities currently available or under exploration for use during pregnancy and lactation. The ultimate aim is to achieve an optimal balance between the risks and benefits of any type of intervention, and to customize treatment on an individual basis in order to achieve the best outcomes for both mother and fetus.

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Investigating the effects of the Rho-kinase enzyme inhibitors AS1892802 and fasudil hydrochloride on the contractions of isolated pregnant rat myometrium

Cited by 7 publications

References 35 publications

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Involvement of α_1B-adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen

Management of glaucoma in pregnancy – balancing safety with efficacy

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Investigating the effects of the Rho-kinase enzyme inhibitors AS1892802 and fasudil hydrochloride on the contractions of isolated pregnant rat myometrium

Cited by 7 publications

References 35 publications

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog

Involvement of α1B-adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen

Management of glaucoma in pregnancy – balancing safety with efficacy

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Product

Resources

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Involvement of α_1B-adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen