Redox modulation of diaphragm contractility Interaction between DHPR and RyR channels

Previous reports indicate that reactive oxygen species (ROS) may modulate contractility in skeletal muscle Although Ca2+-sensitivity of the contractile apparatus appears to be a primary site of regulation dihydropyridine receptor (DHPR or L type Ca2+ channels) and calcium efflux in isolated sarcoplasmic reticulum (SR) vesicles appear to be redox sensitive as well However DHPR as a target is poorly understood in intact muscles at body temperature particularly in the diaphragm a muscle more dependent on external Ca2+ than locomotor muscles Previously we reported that oxidant challenge via xanthine oxidase (XO) alters the K+ contractures in diaphragm fiber bundles suggestive of a role of L-type Ca2+ channels Contractility of isolated rat diaphragm fiber bundles revealed a biphasic response to ROS challenge that was dose and time dependent Potentiation of twitch and low-frequency diaphragm fiber bundle contractility with 0 02 U ml (1) XO was reversible or partially preventable with washout dithiothreitol and the SOD/catalase mimetic EUK 134 The RyR antagonist ruthenium red inhibited xanthine oxidase-Induced potentiation while the RyR agonist caffeine elevated diaphragm twitch and low frequency tension in a non-additive manner by 55% when Introduced simultaneously with ROS challenge The DHPR antagonist nitrendipine (15 mu M) inhibited elevation in low-frequency diaphragm tension produced by ROS challenge Caffeine threshold tension curves were shifted to the left with 0 02 U ml (1) XO but this effect was partially reversed with 15 mu M nitrendipine These results are consistent with the hypothesis that DHPR redox state and RyR function are modulated in an interactive manner affecting contractility in intact diaphragm fiber bundles (C) 2010 Elsevier Inc All rights reserved