β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect

Odnoshivkina, Ulia G.; Sytchev, Vaycheslav I.; Нуруллин, Л. Ф.; Giniatullin, Arthur R.; Зефиров, А. Л.; Petrov, Alexey M.

doi:10.1016/j.ejphar.2015.08.020

Cited by 27 publications

(8 citation statements)

References 48 publications

(47 reference statements)

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“…This is the first report, which shows that activation of the NO/cGMP pathway contributes to the vasodilator effect elicited by midodrine, fenoterol, sitagliptin, and isoxsuprine. The results obtained in the present study, support previous findings, which indicated that the pharmacological effects of fenoterol on tissues other than blood vessels are associated with a rise in NO levels [49,50]. Our results also agree with earlier studies, which demonstrated that sitagliptin, orally administered to diabetic rats, significantly increased NO levels in rat aortas and blood serum [47,51].…”

Section: Discussionsupporting

confidence: 93%

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

et al. 2019

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Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO/cGMP and H2S/KATP signaling pathways and blockade of α1-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 93%

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

et al. 2019

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“…The tocolytics used in our sample were hexoprenaline and phenoterole, beta-2 adrenergic agonists, of which the exact mechanism how they can contribute to ASD risk is not clear yet. Animal studies that explored the effect of prolonged treatment with phenoterole confirmed the increased production of free radicals; however, the studies were oriented towards cardiomyocites, and not neurons (50). In vitro studies, on the other hand, showed that phenoterol might be considered as a substrate for peroxidase, further producing reactive metabolytes, although its main detoxification metabolic pathway is via conjugation (51).…”

Section: Discussionmentioning

confidence: 99%

Autism Spectrum Disorders and Perinatal Complications—Is Oxidative Stress the Connection?

et al. 2019

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Background: Autism spectrum disorders (ASD) are complex psychiatric disorders, with gene environment interaction being in the basis of their etiology. The association of perinatal complications and ASD is well established. Recent findings suggested that oxidative stress and polymorphism in genes encoding antioxidant enzymes might be involved in the development of ASD. Glutathione transferases (GSTs) have an important role in the antioxidant defense system. We aimed to establish whether the predictive effects of prenatal and perinatal complications (as possible oxidative stress inducers) on ASD risk are dependent on GST polymorphisms. Methods: The study included 113 ASD cases and 114 age- and sex group-matched healthy controls. All participants were genotyped for GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms. The questionnaire regarding prenatal and perinatal risk factors and complications was administered for all the subjects in the study. Results: The evaluated perinatal complications as a group significantly increased the risk of ASD [odds ratio (OR) = 9.415; p = 0.000], as well as individual perinatal complications, such as prematurity (OR = 11.42; p = 0.001), neonatal jaundice (OR = 8.774; p = 0.000), respiratory distress syndrome (OR = 4.835; p = 0.047), and the use of any medication during pregnancy (OR = 2.413; p = 0.03). In logistic regression model, adding GST genotypes did not modify the significant effects found for prematurity and neonatal jaundice as risk factors in ASD. However, there was a significant interaction of GST genotype with medication use during pregnancy and the use of tocolytics during pregnancy, which was predictive of ASD risk only in carriers of GSTM1-null, as opposed to carriers of GSTM1-active genotype. Conclusion: Specific perinatal complications may be significant risk factors for ASD. GSTM1 genotype may serve as a moderator of the effect of some prenatal factors on the risk of ASD such as using medication during pregnancy. It may be speculated that different oxidative stress-related genetic and environmental factors could lead to development of ASD. Apart from etiological mechanisms, possible therapeutic implications in ASD are also discussed.

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“…Increased gene expression of various TRP channels (including TRPM, TRPC, TRPV, and TRPP) have been identified in leukocytes of patients with non-valvular AF ( Duzen et al, 2017 ). TRPV channels have been linked to atrial inotropy related to ROS-mediated signaling ( Odnoshivkina et al, 2015 ), and in a porcine model, depletion of TRPV1 afferent fibers resulted in a reduction in ventricular arrhythmic events associated with MI ( Yoshie et al, 2020 ). A study has shown that TRPA1 may be a novel therapeutic target for increasing inotropic and lusitropic states in the heart, having demonstrated that stimulation of TRPA1 in isolated murine cardiomyocytes resulted in activation of CaMKII-dependent signaling and an increase in peak intracellular Ca 2+ levels, driving an increase in cardiomyocyte contractile function ( Andrei et al, 2017 ).…”

Section: Cardiac Arrhythmiasmentioning

confidence: 99%

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

2020

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Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

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β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect

Cited by 27 publications

References 48 publications

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

Autism Spectrum Disorders and Perinatal Complications—Is Oxidative Stress the Connection?

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

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