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.