Addition of nitric oxide donor S-nitroso-N-acetylcysteine to selective iNOS inhibitor 1400W further improves contractile function in reperfused skeletal muscle

Abstract

This study examines the effects of combination therapy with the nitric oxide (NO) donor S-nitroso-N-acetylcysteine (SNAC) and the iNOS inhibitor N-(3-(aminomethyl)benzyl) acetamidine (1400W) on contractile function in reperfused rat skeletal muscle. The right extensor digitorum longus (EDL) muscles of 104 rats were subjected to 3 h of ischemia followed by reperfusion times of 3 h, 24 h, and 7 days. For each time period, rats were further divided into sham operation, control, 1400W only, and 1400W plus SNAC groups. In vitro muscle contractile functional testing was performed in an organ chamber with electrical stimulation. The results showed that twitch and isometric tetanic forces were significantly improved in the 1400W-alone group compared to controls for 24 h and 7 days, but not 3 h of reperfusion. However, all three time periods of reperfusion showed that combination treatment of 1400W + SNAC significantly improved muscle contractile force compared to both control and 1400W-only groups. This corresponded to the decreased tissue necrosis and inflammation seen with combination therapy histologically. Our results demonstrate that combination treatment of 1400W + SNAC promotes functional recovery in reperfused skeletal muscle, supporting that manipulation of NO levels with a NO donor and an iNOS inhibitor is more beneficial than either treatment in isolation.

Interactions between inducible nitric oxide synthase and cyclooxygenase‐2 in response to ischaemia‐reperfusion of rabbit bladder

“…The increase in iNOS activity in the present study is clearly time-dependent, which complies with the finding that iNOS protein and catalytic activity were detectable in rat brain 12 h after cerebral ischaemia, with the peak at 48 h and return to the baseline at 168 h [18]. iNOS up-regulation by pro-inflammatory cytokines is directly associated with I/R injury in a wide variety of tissues including bladder [4], skeletal muscle [19], kidney [20], brain [21], etc. A high level of NO derived from iNOS has been reported to react with superoxide generated during reperfusion, and generate the highly toxic peroxynitrite anion, leading to tissue injury with further cytokine and inflammatory mediator production.…”

“…The above possible mechanism for the induction of iNOS is a positive feedback loop [19]. Recently, treatment with 1400W as an iNOS inhibitor has been reported to ameliorate I/R injury [19–21]. In the present study, 1400W significantly suppressed the increase in iNOS enzymatic activity after I/R but failed to affect the cNOS activity, suggesting that 1400W at this dose acts as an iNOS‐selective inhibitor.…”

Treatment of Tourniquet-Induced Ischemia Reperfusion Injury with Muscle Progenitor Cells

“…Previous studies by others showed that by using variety types of treatments, muscle injury caused by 3 h TK could be reduced at acute time points of 1, 2, 3, 4, 24, 48 h, and 7 d [9,[33][34][35][36][37][38][39][40][41]. However, there is a lack of a study showing beneficial effects of any treatment that lasts for a longer time period.…”

Optimal Temperature for Hypothermia Intervention in Mouse Model of Skeletal Muscle Ischemia Reperfusion Injury

“…Traditionally, rubber band tourniquets and vascular clips have been used to induce ischemia in mouse hindlimb. 3,7,9,10,23,25 However, both methods have certain disadvantages. Rubber bands may induce crushing injury to the tissue due to the high local compression, 5 and vascular clips require surgeries which may induce more variability and complications.…”