The effect of chelerythrine on depolarization-induced force responses in skinned fast skeletal muscle fibres of the rat.
1 We examined the effect of the protein kinase C (PKC) inhibitor chelerythrine on depolarization-induced force responses (DIFRs) and sarcoplasmic reticulum (SR) function in single, mechanically skinned skeletal muscle fibres of the rat. 2 In this study, the DIFRs in the skinned fibres normally underwent an irreversible loss of excitation-contraction coupling (ECC) after 10-15 responses. Chelerythrine (12 micro M) was shown to restore ECC in these fibres. Restored force responses were similar in peak (control 50.8+/-6.4%, chelerythrine 56.9+/-12.4% of maximum force, P=0.42, n=21), but significantly broadened compared to initial control responses (full-width at half maximum, control; 3.7+/-0.3 s, chelerythrine; 13.3+/-1.1 s, P<0.001). Early exposure to chelerythrine prevented run-down of DIFRs. Chelerythrine also induced spontaneous force responses in some fibres. 3 The PKC inhibitors calphostin C and staurosporine did not restore ECC, and the PKC activator phorbol 12-myristate 13-acetate did not promote loss of ECC in the skinned fibres. 4 Chelerythrine significantly increased SR Ca(2+) loading by 8.4+/-1.7% (P=0.02, n=9) and SR Ca(2+) release by at least 14.1+/-2.7% (P=0.004, n=11) in the skinned fibres. 5 Chelerythrine had no significant effect on maximum force production or the [Ca(2+)] producing half maximal activation of the myofilaments. However, chelerythrine did have a small effect on the slope of the force-Ca(2+) relationship (P=0.02, n=10). 6 Chelerythrine reverses the use-dependent loss of excitation-contraction coupling in skinend skeletal muscle fibres by a PKC independent pathway. Chelerythrine may be an important pharmacological probe for examining the mechanisms of contraction-induced muscle injury.
Han
Renzhi
R
School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Australia.
Bakker
Anthony J
AJ
D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D010617:Phenanthridines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology
D000470:Alkaloids; D053119:Benzophenanthridines; D010617:Phenanthridines; D002110:Caffeine; C016299:chelerythrine; D011493:Protein Kinase C; D002118:Calcium