title: L-type Ca2+ channel and Na+/Ca2+ exchange inhibitors reduce Ca2+ accumulation in reperfused skeletal muscle.
abstract: It is known that extracellular Ca2+ accumulates within skeletal muscle after prolonged periods of ischemia and reperfusion. In this study, we determined whether the L-type Ca2+ channel and the Na+/Ca2+ exchanger mediated Ca2+ influx and whether Ca2+ accumulation limited the metabolic and contractile recovery of reperfused skeletal muscle. Contracting rat hindlimbs (1-Hz twitch) exposed to 40 min of no-flow ischemia were reperfused with diltiazem (500 microM) or 3,4-dichlorobenzamil (300 microM) to block the Na+/Ca2+ exchanger and/or the L-type Ca2+ channel. High inhibitor concentrations were used to counter the binding of diltiazem and 3,4-dichlorobenzamil to albumin and red blood cells. Muscle Ca2+ accumulation, contractile function, and energy metabolism were assessed by measuring intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, twitch tension, and high-energy phosphagens [ATP, total adenine nucleotides (TAN) and phosphocreatine (PCr)]. Compared with control reperfusion, diltiazem and 3,4-dichlorobenzamil reduced Ca2+ influx and attenuated the rise in [Ca2+]i in the fast-oxidative glycolytic plantaris (Pl) and the fast-glycolytic white gastrocnemius (WG). The inhibitor-induced decrease in Ca2+ influx was 1.5- to 2-fold greater with 3,4-dichlorobenzamil than with diltiazem. Coinciding with the reduced Ca2+ accumulation, diltiazem and 3,4-dichlorobenzamil enhanced the resynthesis of ATP (Pl and WG), PCr (Pl and WG), and TAN (Pl) compared with control reperfusion. 3,4-Dichlorobenzamil also augmented twitch-tension recovery. We conclude that Ca2+ accumulation during reperfusion 1) arises from L-type Ca2+ channel and Na+/Ca2+ exchange activation; and 2) impairs the metabolic and contractile recovery of skeletal muscle.
authors.affiliation: Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.
authors.forename: D G
authors.initials: DG
authors.lastname: Welsh
authors.forename: M I
authors.initials: MI
authors.lastname: Lindinger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D000255:Adenosine Triphosphate; D012964:Sodium; D002118:Calcium