Na<sup>+</sup>/H<sup>+</sup>exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

McAllister, Sandra E.; Moses, Michael A.; Jindal, Kunaal; Ashrafpour, Homa; Cahoon, Neil J.; Huang, Ning; Neligan, Peter C.; Forrest, Christopher R.; Lipa, Joan E.; Pang, Cho Y.

doi:10.1152/japplphysiol.91069.2008

Cited by 14 publications

(5 citation statements)

References 65 publications

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“…The final cellular damage is then due to calcium overload, the paradigm of ischemia-reperfusion damage. This mechanism is well-known to occur in the heart [34][35][36] and skeletal muscle [44,45] where abrupt reperfusion follows a brief episode of total ischemia. Ischemia alone in this situation of ischemia/reperfusion situation is too short to cause damage but reperfusion strongly activates the NHE1 and the reverse mode of the NCX to cause damage via calcium overload.…”

Section: What Are the Mechanisms That Could Cause Sodium Loading In Me/cfs?mentioning

confidence: 99%

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Wirth¹,

Scheibenbogen

2021

J Transl Med

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Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

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Section: What Are the Mechanisms That Could Cause Sodium Loading In Me/cfs?mentioning

confidence: 99%

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Wirth¹,

Scheibenbogen

2021

J Transl Med

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“…Indeed, prolonged IR in skeletal muscle has been found to significantly impair mitochondrial respiratory chain complex activities (6,44), reduce adenosine diphosphate-activated respiratory activity (state 3), decrease inner membrane potential and basal respiration (3,34), and increase cytosolic/mitochondrial calcium overload (10,26). Before cell death, increased radical oxygen species (ROS) induce cell membrane alterations, edema (18), and microvascular lesions (41).…”

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confidence: 99%

Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion

Talha

Bouitbir

Charles

et al. 2013

Journal of Applied Physiology

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Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 ± 0.3 vs. 5.8 ± 0.2 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 ± 0.8 vs. 13.7 ± 0.9 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 ± 0.1 vs. 0.7 ± 0.1, P < 0.05) and oxidative stress (+45%, 9,067 ± 935 vs. 6,249 ± 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5-hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels.

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“…Many medical treatment options such as recombinant human BCL2 protein, ethyl pyruvate, laser therapy, hydrogen sulfide, PJ 34, poloxamer 188, ketamine, recombinant human VEGF165 protein, activated protein C, adenosine A, bortezomib, MRS2693, hypertonic saline solution, cariporide, grape seed proanthocyanin extract, Wisconsin solution, ultrasound, erythropoietin, resveratrol, vitamin E, 12 amino acid peptides have been experimentally studied and all of them were reported to have positive effects at some degree. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] However, studies on all these agents remained experimental and these agents failed to find a place in clinical use.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Ischemic Preconditioning and Systemic Piracetam for Prevention of Ischemia-Reperfusion Injury in Musculocutaneous Flaps

Demiröz

Derebaşınlıoğlu

Ercan

et al. 2020

J Reconstr Microsurg

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Background Ischemia-reperfusion injury plays an important role in flap failure. Ischemic preconditioning technique is the only proven method for preventing ischemia-reperfusion injury, but it is not used widely in daily practice because of difficulties such as prolonging the operation time, need for surgical experience, and increasing the risk of complications. This study has been performed with the assumption that piracetam may be a simple and inexpensive alternative to the preconditioning technique due to its antioxidant, antiaggregant, rheological, anti-inflammatory, antiapoptotic, cytoprotective, and immune modulating effects. Methods Thirty-two rats were divided into four groups and latissimus dorsi musculocutaneous flaps were raised. No extra procedure was applied, and no treatment was given to the control group. Four hours of ischemia was created by clamping the thoracodorsal pedicle in the second group. The animals in the third group were treated with 10 minutes of ischemia and reperfusion periods as a preconditioning procedure before the 4 hours of ischemia. Animals in the fourth group received systemic piracetam 30 minutes before and 6 days after reperfusion. Nitric oxide and myeloperoxidase levels in serum and tissue, acute inflammatory cell response, and vascular proliferation in tissue were examined at the postoperative 24th hour and 10th day. Results Myeloperoxidase activity in both preconditioning and piracetam groups, was significantly lower than the ischemia-reperfusion group. Acute inflammatory cell response was similarly decreased in both preconditioning and piracetam groups compared with ischemia-reperfusion group. Tissue measurements of nitric oxide were also significantly higher in both preconditioning and piracetam groups than in the ischemia-reperfusion group. However, vascular proliferation increased in the preconditioning group, while it did not show any significant change in the piracetam group. Conclusion This study shows that systemic piracetam treatment provides protection against ischemia-reperfusion injury in musculocutaneous flaps and can offer a simple and inexpensive alternative to the preconditioning technique.

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Na⁺/H⁺exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

Cited by 14 publications

References 65 publications

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion

Comparison of Ischemic Preconditioning and Systemic Piracetam for Prevention of Ischemia-Reperfusion Injury in Musculocutaneous Flaps

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Na+/H+exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

Cited by 14 publications

References 65 publications

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion

Comparison of Ischemic Preconditioning and Systemic Piracetam for Prevention of Ischemia-Reperfusion Injury in Musculocutaneous Flaps

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Product

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Na⁺/H⁺exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion