Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

Almukhtar, Hani; Garle, Michael J.; Smith, Paul A.; Roberts, Richard E.

doi:10.1016/j.taap.2016.06.024

Cited by 8 publications

(6 citation statements)

References 66 publications

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“…Based on data from respiration studies on intact mitochondria, it is argued that Complex I is the primary target for simvastatin (Sirvent, Bordenave, et al, 2005); an idea support by the similarly of the effects of rotenone, a selective complex I inhibitor, to simvastatin in the present study. The inability of hydrophilic pravastatin to affect mitochondrial function is consistent with that previously reported for murine beta-cells (Zhou et al, 2014) and porcine coronary artery (Almukhtar et al, 2016).…”

Section: Discussionsupporting

confidence: 90%

“…Consequently an impairment in mitochondrial function is expected to decrease VGCC activity and Ca 2+ influx, events that will suppress insulin secretion. Indeed a similar mechanism has already been proposed to explain the decrease in artery vascular smooth muscle tone seen with statins (Almukhtar et al, 2016); a tissue in which VGCCs are also modulated by ATP and mitochondrial respiration (McHugh and Beech, 1996;Ohya and Sperelakis, 1989).…”

Section: Introductionmentioning

confidence: 59%

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Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function

Curry

Almukhtar

Alahmed

et al. 2019

Toxicological Sciences

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Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognised "off-targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolaemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells since mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca 2+ influx via opening of voltage-gated Ca 2+ channels (VGCCs).We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption and ATP-sensitive-K + -channel activity were monitored as markers of mETC activity, respiration and cellular ATP/ADP ratio respectively; Ca 2+ channel activity and Ca 2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 ~ 3 µM) and mETC (1< IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar's absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 59%

Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function

Curry

Almukhtar

Alahmed

et al. 2019

Toxicological Sciences

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“…Fluoxetine, bupropion, dothiepin, maprotiline, mianserin, trimipramine, monoamine oxidase-B (MAO-B) inhibitors, imipramine, amitriptyline, and mirtazapine, have been shown to have antiulcer properties 4,56 . In animal models, higher susceptibility to depression and anxiety is linked to ulceration, the same will be valid in human beings 7,8 . Furthermore, typical antidepressants and anxiolytics can greatly minimize the onset of stress ulcers, possibly to a significant degree than typical therapy like cimetidine and antacids 9,10 .…”

Section: Introductionmentioning

confidence: 86%

Fluvoxamine Provide a Gastro-Protection Against Vitiated Insult

Sada W. Abdulqader,

Ibrahim M. Faisal,

M. G. Saeed

et al. 2021

Indian Journal of Forensic Medicine & Toxicology

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The etiology of peptic ulcer disease is multifactorial and remains an enigma over the last decades. The central parameter is the acid secretion; whose control is under the coordination of gastrin, acetylcholine, histamine, and prostaglandin. The treatment of peptic ulcers is a bi-armed tool, directed toward fighting microbial growth alongside acid suppression. However recent studies reported failure of the therapy due to recurrence of symptoms. Therefore, additional parameters should be considered including patient mood and psychological status. The present study aimed to introduce a new approach to the therapeutic regimen of ulcer disease using commonly used antidepressant drugs (fluvoxamine and fluoxetine) in a laboratory animal model of peptic ulcer induced by stress insult to act as a mood upset model in an attempt to mimic mood changes in human. The study was conducted on 4 groups of laboratory animals using control negative and control positive (misoprostol) against the tested drugs group (fluvoxamine and fluoxetine group). The result confirmed that fluvoxamine confers gastroprotective effects against ulcer insult compared to both fluoxetine or misoprostol groups. These results might significantly mean that antidepressant drugs could be utilized in peptic ulcer diseases or added at low doses to prevent ulcer insults due to whatever precipitating factors, such as, infection, alcohol, smoking, NSAIDs, and stress ulcer.

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“…The vessels were then washed 3x with 5 ml DMEM (D6429, Sigma-Aldrich, Dorset, UK) containing 1X antibiotic antimycotic solution in a 30 ml universal tube. To isolate smooth muscle cells, each vessel was incubated at 37 °C for 40 min in a 1.5 ml Eppendorf containing 1 ml DMEM with type II collagenase (2mg/mL, C6885, Sigma-Aldrich, Dorset, UK) [24]. Each vessel was then washed twice with 1 ml DMEM, 1X antibiotic antimycotic solution.…”

Section: Cultured Porcine Coronary Artery Smooth Muscle Cellsmentioning

confidence: 99%

A critical role for cystathionine-β-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery

Donovan

Wong

Roberts

et al. 2017

Vascular Pharmacology

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Hypoxia-induced coronary artery vasodilatation protects the heart by increasing blood flow under ischemic conditions, however its mechanism is not fully elucidated. Hydrogen sulfide (HS) is reported to be an oxygen sensor/transducer in the vasculature. The present study aimed to identify and characterise the role of HS in the hypoxic response of the coronary artery, and to define the HS synthetic enzymes involved. Immunoblotting and immunohistochemistry showed expression of all three HS-producing enzymes, cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), in porcine coronary artery. Artery segments were mounted for isometric tension recording; hypoxia caused a transient endothelium-dependent contraction followed by prolonged endothelium-independent relaxation. The CBS inhibitor amino-oxyacetate (AOAA) reduced both phases of the hypoxic response. The CSE inhibitor dl-propargylglycine (PPG) and aspartate (limits MPST) had no effect alone, but when applied together with AOAA the hypoxic relaxation response was further reduced. Exogenous HS (NaS and NaHS) produced concentration-dependent contraction followed by prolonged relaxation. Responses to both hypoxia and exogenous HS were dependent on the endothelium, NO, cGMP, K channels and Cl/HCO exchange. HS production in coronary arteries was blocked by CBS inhibition (AOAA), but not by CSE inhibition (PPG). These data show that HS is an endogenous mediator of the hypoxic response in coronary arteries. Of the three HS-producing enzymes, CBS, expressed in the vascular smooth muscle, appears to be the most important for HS generated during hypoxic relaxation of the coronary artery. A contribution from other HS-producing enzymes only becomes apparent when CBS activity is inhibited.

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Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

Cited by 8 publications

References 66 publications

Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function

Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function

Fluvoxamine Provide a Gastro-Protection Against Vitiated Insult

A critical role for cystathionine-β-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery

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