Verapamil regulation of a defective SR release channel in the cardiomyopathic Syrian hamster.
The Bio 14.6 Cardiomyopathic Syrian Hamster (CMH) has an autosomal recessive disease characterized by intracellular calcium overload, cardiac and skeletal myopathies and premature death from congestive heart failure. Early treatment of these animals with the calcium antagonist, verapamil (V), prevents the development of the disease. We have previously provided evidence supporting a specific defect in the ryanodine-sensitive SR calcium release channel (SRCRC) in CMH. We now provide physiologic and biochemical evidence that V modulates SRCRC. Papillary muscles prepared from F1B control hamsters (F1B) revealed an enhanced inotropic responsiveness to V and ryanodine (R) with age, not seen with CMH. CMH papillary muscles demonstrated paradoxical positive inotropic effects of V and R not shared with F1B. The positive inotropic effects of V and R were not additive. V enhanced the affinity (decreased KD) of [3H]ryanodine binding to cardiac membranes. Thus, V may prevent the overt manifestations of genetic disease in CMH by modulating a defective ryanodine-sensitive SR release channel.
Finkel
M S
MS
Department of Medicine, University of Pittsburgh School of Medicine.
Shen
L
L
Oddis
C V
CV
Romeo
R C
RC
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D006224:Cricetinae; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007700:Kinetics; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D011869:Radioligand Assay; D012433:Ryanodine / Q000378:metabolism / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000648:ultrastructure*; D012680:Sensitivity and Specificity; D013268:Stimulation, Chemical; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology*
D015220:Calcium Channels; D002316:Cardiotonic Agents; D014316:Tritium; D012433:Ryanodine; D014700:Verapamil; D002118:Calcium