Effect of the organic Ca2+ channel blocker D-600 on sarcoplasmic reticulum Ca2+ uptake in skeletal muscle.
Experiments were undertaken to study the possibility that the calcium channel blocker D-600 (gallopamil), which penetrates into muscle cells (20), facilitates excitation-contraction coupling in skeletal muscle (7) by a direct effect on the sarcoplasmic reticulum (SR). The effects of D-600 were studied on single phasic muscle fibers, either intact or split open. D-600 potentiated twitches in intact fibers at concentrations lower than those reported in whole muscles. In split fibers, the force produced by caffeine-induced Ca2+ release from the SR was reversibly inhibited by 5 microM D-600, when added to the Ca2+ loading solution. This inhibitory effect was inversely related to temperature, and it was dose dependent. When D-600 was added after Ca2+ loading and before caffeine exposure, or during the caffeine exposure itself, it did not inhibit Ca2+ release, but rather increased the development of force. We conclude that, apart from the blocking effect that D-600 may have on the voltage sensor, the drug penetrates into the myoplasm and affects excitation-contraction coupling by inhibiting the SR Ca2+ pump. This may be the consequence of a conformational change in the transmembrane Ca2+ binding domain of the ATPase.
Ortega
A
A
Department of Physiology, University of Maryland, Baltimore 21201, USA.
Gonzalez-Serratos
H
H
Lepock
J R
JR
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005711:Gallopamil / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D011896:Rana temporaria; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature
D002121:Calcium Channel Blockers; D005711:Gallopamil; D002110:Caffeine; D002118:Calcium