Aim: Investigate the possible effect of H2S on skeletal muscle in cast immobilization model of hindlimbs in rats and the role of ATP sensitive K channels in the mechanism of action of H2S on skeletal muscle. Methodology: This study was conducted on 40 adult male rats weighing 180-250 grams. Rats were divided into 4 groups: Group (I) (Immobilized group) (I group) Group (II) (Immobilized and H2S group) (IH group) Group (III) (Immobilized with combined H2S and ATP sensitive K channels blocker group) (IHG group). All the three groups were maintained with plaster cast for two weeks. A group of negative control rats that not immobilized, not receiving any drugs were used Group (IV) (negative control group) (C group). At the end of the 2 weeks, the rats were sacrificed. Then, casts in immobilized groups were removed to obtain tibialis anterior muscles from immobilized and contralateral limbs. Biochemical, histopathological, and immunohistopathological examination were studied. Results: The immobilized group showed significant deterioration in the contractile parameters and significant atrophic changes in tibialis anterior muscles. NAHS supplementation in (IH gp) can help in protection against myopathy as it showed significant alleviation of atrophic changes in tibialis anterior muscles. Addition of glibenclamide to NAHS treatment to immobilized rats (IHG gp) led to similar changes in tibialis anterior muscles as the immobilized group. Conclusion It is possible to conclude that H2S has a protective role in the cast immobilization rat model and it exerts its actions mainly through opening the ATP sensitive K+ channels
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