Nitric oxide synthase inhibition affects sarcoplasmic reticulum Ca2+ release in skeletal muscle fibres from mouse.
Nitric oxide (NO) generated by skeletal muscle is believed to regulate force production but how this is achieved remains poorly understood. In the present work we tested the effects of NO synthase (NOs) inhibitors on membrane current and intracellular calcium in isolated skeletal muscle fibres from mouse, under voltage-clamp conditions. Resting [Ca(2+)] and [Ca(2+)] transients evoked by large depolarizations exhibited similar properties in control fibres and in fibres loaded with tenth millimolar levels of the NOs inhibitor N-nitro-L-arginine (L-NNA). Yet the voltage dependence of calcium release was found to be shifted by approximately 15 mV towards negative values in the presence of L-NNA. This effect could be reproduced by the other NOs inhibitor S-methyl-L-thiocitrulline (L-SMT). Separate experiments showed that the voltage dependence of charge movement and of the slow calcium current were unaffected by the presence of L-NNA, ruling out an effect on the voltage sensor. A negative shift in the voltage dependence of calcium release with no concurrent alteration in the properties of charge movement was also observed in fibres exposed to the oxidant H(2)O(2) (1 mM). Conversely the reducing agent dithiothreitol (10 mM) had no obvious effect on Ca(2+) release. Overall, the results indicate that physiological levels of NO exert a tonic inhibitory control on the activation of the calcium release channels. Changes in the voltage dependence of Ca(2+) release activation may be a ubiquitous physiological consequence of redox-related modifications of the ryanodine receptor.
Physiologie Intégrative Cellulaire et Moléculaire, Université Claude Bernard - Lyon 1, UMR CNRS 5123, Villeurbanne, France.
Sandrine
S
Pouvreau
Vincent
V
Jacquemond
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D019335:Nitroarginine; D002956:Citrulline; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013890:Thiourea; C086717:S-methylthiocitrulline; C048960:indo-1; D002118:Calcium