Related Experiment Videos
Possible functional linkage between the cardiac dihydropyridine and ryanodine receptor: acceleration of rest decay by
E McCall1, L V Hryshko, V M Stiffel
1Department of Physiology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Insights
The L-Type Ca channel agonist Bay K 8644 accelerates calcium loss from the sarcoplasmic reticulum in heart muscle. This occurs through a direct interaction with ryanodine receptors, impacting cardiac contractility.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Calcium Signaling
Background:
- Post-rest contractions in cardiac muscle exhibit potentiation and decay.
- L-Type Ca channel agonists influence cardiac excitation-contraction coupling.
Purpose of the Study:
- Investigate the effect of Bay K 8644 on post-rest contractions in ferret ventricular muscle.
- Elucidate the mechanism by which Bay K 8644 alters sarcoplasmic reticulum (SR) Ca handling during rest.
Main Methods:
- Electrophysiological recordings of post-rest contractions and action potentials.
- Voltage-clamp measurements of ionic currents.
- Caffeine- and rapid cooling-induced contractures to assess SR Ca content.
- Ryanodine binding assays in isolated myocytes.
Main Results:
- Bay K 8644 abolished rest potentiation and accelerated rest decay, independent of extracellular Ca or L-type Ca current (ICa).
- SR Ca content declined more rapidly in the presence of Bay K 8644.
- Bay K 8644 increased ryanodine receptor binding, suggesting a direct interaction with the SR Ca release channel.
Conclusions:
- Bay K 8644 accelerates resting Ca loss from the SR by potentially altering the physical linkage between the dihydropyridine receptor and ryanodine receptors.
- This interaction increases SR Ca release channel opening during rest, impacting cardiac function.
Abstract:
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).