Possible functional linkage between the cardiac dihydropyridine and ryanodine receptor: acceleration of rest decay by Bay K 8644.
The effect of the dihydropyridine L-Type Ca chanel agonist Bay K 8644 on post-rest contractions in ferret ventricular muscle and isolated myocytes was investigated. Bay K 8644 was shown to abolish rest potentiation and greatly accelerate rest decay. The post-rest contraction suppressed by Bay K 8644 was accompanied by action potentials of large amplitude and longer duration, but voltage-clamp measurements showed that this suppression was not due to a supra-optimal ICa trigger. Caffeine-induced contractures and rapid cooling contractures demonstrated an accelerated rest-dependent decline in sarcoplasmic reticulum (SR) Ca content in the presence of Bay K 8644, which was present even with Ca-free superfusion during rest. Thus, the Bay K 8644-induced decline of SR Ca during rest was independent of extracellular Ca or ICa. To explore whether the binding of Bay K 8644 to the dihydropyridine receptor could alter the SR Ca release channel/ryanodine receptor in a more direct way, ryanodine binding was measured in the absence and presence of Bay K 8644. Ryanodine binding to isolated ferret ventricular myocytes was increased by Bay K 8644 under conditions where sarcolemmal-SR junctions might be expected to be intact, but not after physical disruption. These results are consistent with a working hypothesis where Bay K 8644 may bind to the dihydropyridine receptor and this may lead to physical changes in the linkage between the dihydropridine receptor and a subset of ryanodine receptors, thereby increasing the opening of the SR Ca release channel during rest (and accelerating resting Ca loss).
McCall
E
E
Department of Physiology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Hryshko
L V
LV
Stiffel
V M
VM
Christensen
D M
DM
Bers
D M
DM
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D005289:Ferrets; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D017275:Isradipine / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009124:Muscle Proteins / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D011869:Radioligand Assay; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium; D017275:Isradipine