Differential contractile impairment of fast- and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure.
Congestive heart failure (CHF) is associated with exercise intolerance that cannot be entirely explained by hypoperfusion of the skeletal muscles. We studied the contractile properties of fast-twitch (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) skeletal muscles in doxorubicin-induced CHF in rats, and evaluated the defective steps of excitation-contraction coupling. Both types of muscles-obtained from CHF rats displayed significant reduction in twitch and tetanic contractions. Twitch half-relaxation times of CHF SOL muscles were prolonged while there was no significant difference in EDL muscles. High K(+) application induced lower contracture amplitudes in CHF muscles. Caffeine-induced contractures were significantly diminished in CHF SOL. Verapamil application depressed tetanic contractions in all preparations while depression was more pronounced in CHF SOL. Immunohistochemistry revealed reduced expression of sarcoplasmic reticulum Ca(2+)-ATPase-1 and -2 in CHF EDL and in CHF SOL, respectively. Sarcolemmal excitability and spontaneous neurotransmitter release were unaffected since resting membrane potential, action potential and miniature end-plate potentials were unaltered in CHF muscles. We conclude that CHF induces contractile impairment that occurs predominantly in rat slow-twitch skeletal muscles. Our results suggest that this muscle-type-specific effect of CHF is related to the defective intracellular Ca(2+) release and uptake mechanisms and reduced sarcolemmal-dihydropyridine-sensitive Ca(2+) channel activity.
Department of Pharmacology Faculty of Medicine, Hacettepe University, Ankara, Turkey. ertunc@hacettepe.edu.tr
Mert
M
Ertunc
Yildirim
Y
Sara
Petek
P
Korkusuz
Rustu
R
Onur
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D002110:Caffeine; D004317:Doxorubicin; D014700:Verapamil; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D011188:Potassium