L-type ca2+ channel and na+/ca2+ exchange inhibitors reduce ca2+
accumulation in reperfused skeletal muscle.
Welsh, Donald G., and Michael I. Lindinger.
Dept. of Human Biology and Nutritional Sciences, University of
Guelph, Guelph, Ontario, Canada, N1G 2W1
APStracts 2:0518A, 1995.
It is known that extracellular calcium accumulates within skeletal
muscle following prolonged periods of ischemia and reperfusion. In
this study, we determined if the L-type Ca2+ channel and the Na+/Ca2+
exchange mediated Ca2+ influx and if 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 uM) or 3,4
-dichlorobenzamil (300 uM) in order to block the Na+/Ca2+ exchange
and/or the L-type Ca2+ channel. High inhibitor concentrations were
used to counter the binding of diltiazem and dichlorobenzamil to
albumin and erythrocytes. Muscle Ca2+ accumulation, contractile
function, and energy metabolism were assessed by measuring
intracellular Ca2+ (Ca2+i), Ca2+ influx, twitch tension, and high
energy phosphagens (ATP, total adenine nucleotides (TAN),
phosphocreatine (PCr)). Compared to control reperfusion, diltiazem
and 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 1.5-2 fold greater with dichlorobenzamil than with
diltiazem. Coinciding with the reduced Ca2+ accumulation, diltiazem
and dichlorobenzamil enhanced the resynthesis of ATP (Pl and WG), PCr
(Pl and WG) and TAN (Pl) compared to control reperfusion.
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.
Received 23 June 1995; accepted in final form 14 November 1995.
APS Manuscript Number A674-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 8 December 95