Uterus‐relaxing effect of β2‐agonists in combination with phosphodiesterase inhibitors: Studies on pregnant rat in vivo and on pregnant human myometrium in vitro

Verli, Judit; Klinke, Anna; Kormányos, Zsolt; Hajagos-Tóth, Judit; Ducza, Eszter; Seres, Adrienn B.; Falkay, George; Gáspár, Róbert

doi:10.1111/j.1447-0756.2012.01929.x

Cited by 18 publications

(22 citation statements)

References 36 publications

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“…The results were consistent with the findings of a study using rolipram [30], a selective PDE-4 inhibitor, and forskolin, both induced an increase of cAMP by inhibition of PDE-4 in the near-term human myometrium. The thalidomide analogs inhibited the PGF2α-, K + - and Ca 2+ -induced contractions in a concentration-dependent manner, which indicates that both analogs have similar actions to rolipram in potency and efficacy, suggesting that both analogs may recognize the same isoforms of PDE-4s [1730]; then, although there were minor differences in potency of both analogs and rolipram, it is possible that they share the same targets in pregnant rats as they did in human pregnant myometrium [6]. …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the inhibition of PDE-4 to increase the cAMP has been suggested as a more specific and safer pharmacological approach for the preterm birth treatment. PDE-4 inhibitors such as rolipram, cilomilast, and roflumilast have been studied in diverse preterm birth models [71217]. In fact, a family of non-teratogenic thalidomide analogs are potent PDE-4 inhibitors as well as they are more effective as immunomodulatory and anti-inflammatory agents because they inhibit TNF-α significantly, such as apremilast [61819202122].…”

Section: Introductionmentioning

confidence: 99%

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Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Muñoz-Pérez

Fernández-Martínez

Ponce‐Monter

et al. 2017

Korean J Physiol Pharmacol

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The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1β uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Muñoz-Pérez

Fernández-Martínez

Ponce‐Monter

et al. 2017

Korean J Physiol Pharmacol

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“…Agents that increase intracellular cAMP levels, including forskolin, cAMP-phosphodiesterase (PDE) type 4 inhibitors, and 8-bromo-cAMP, dose dependently inhibit human full-term nonlaboring myometrial contractile force by up to 100% (13,64,128,142,172,218,243,248). It is probable that myometrial cAMP signaling causes MYPT1 serine phosphorylation.…”

Section: )mentioning

confidence: 98%

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Butler

Paul

Europe-Finner

et al. 2013

American Journal of Physiology-Cell Physiology

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The degree of phosphorylation of myosin light chain 20 (MLC20) is a major determinant of force generation in smooth muscle. Myosin phosphatases (MPs) contain protein phosphatase (PP) 1 as catalytic subunits and are the major enzymes that dephosphorylate MLC20. MP regulatory targeting subunit 1 (MYPT1), the main regulatory subunit of MP in all smooth muscles, is a key convergence point of contractile and relaxatory pathways. Combinations of regulatory mechanisms, including isoform splicing, multiple phosphorylation sites, and scaffolding proteins, modulate MYPT1 activity with tissue and agonist specificities to affect contraction and relaxation. Other members of the PP1 family that do not target myosin, as well as PP2A and PP2B, dephosphorylate a range of proteins that affect smooth muscle contraction. This review discusses the role of phosphatases in smooth muscle contractility with a focus on MYPT1 in uterine smooth muscle. Myometrium shares characteristics of vascular and other visceral smooth muscles yet, during healthy pregnancy, undergoes hypertrophy, hyperplasia, quiescence, and labor as physiological processes. Myometrium presents an accessible model for the study of normal and pathological smooth muscle function, and a better understanding of myometrial physiology may allow the development of novel therapeutics for the many disorders of myometrial physiology from preterm labor to dysmenorrhea.

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“…A-kinase anchoring proteins (AKAPs) – protein kinase A (PKA) disruptors – enhance the relaxing effect of β 2 -adrenergic agonists (35). The combination of β 2 -adrenergic agonists with Ca 2+ channel blockers (36) and phosphodiesterase inhibitors (37) were also investigated in preclinical conditions and beneficial co-actions were found. The effectiveness of the therapy with beta-mimetics influences the genotype of the β 2 -receptor.…”

Section: Physiological Factors and Therapeutic Targets Of Pregnant Utmentioning

confidence: 99%

Obesity in pregnancy: a novel concept on the roles of adipokines in uterine contractility

et al. 2017

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Obesity is a global health problem even among pregnant women. Obesity alters quality of labor, such as preterm labor, prolonged labor, and higher oxytocin requirements in pregnant women. The most important factors to play a role in the altered gestational period and serve as drug targets to treat the consequences are female sexual hormones, calcium channels, adrenergic system, oxytocin, and prostaglandins. However, we have limited information about the impact of obesity on the pregnant uterine contractility and gestation time. Adipose tissue, which is the largest endocrine and paracrine organ, especially in obesity, is responsible for the production of adipokines and various cytokines and chemokines, and there are no reliable data available describing the relation between body mass index, glucose intolerance, and adipokines during pregnancy. Recent data suggest that the dysregulation of leptin, adiponectin, and kisspeptin during pregnancy contributes to gestational diabetes mellitus and pre-eclampsia. A preclinical method for obese pregnancy should be developed to clarify the action of adipokines and assess their impact in obesity. The deeper understanding of the adipokines-induced processes in obese pregnancy may be a step closer to the prevention and therapy of preterm delivery or prolonged pregnancy. Gestational weight gain is one of the factors that could influence the prenatal development, birth weight, and adiposity of newborn.

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Uterus‐relaxing effect of β₂‐agonists in combination with phosphodiesterase inhibitors: Studies on pregnant rat in vivo and on pregnant human myometrium in vitro

Abstract: A combination of selective PDE4 inhibitors and β(2) -agonists should be considered for the treatment of preterm contractions.

Cited by 18 publications

References 36 publications

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

Obesity in pregnancy: a novel concept on the roles of adipokines in uterine contractility

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