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BAY K 8644 depresses excitation-contraction coupling in cardiac muscle
1Department of Physiology, Loyola University Medical Center, Maywood, Illinois 60152, USA.
Insights
The dihydropyridine L-type Ca channel agonist BAY K 8644 (BAY) reduces the effectiveness of calcium current in triggering heart muscle contractions. This occurs despite maintaining sarcoplasmic reticulum calcium stores, suggesting BAY alters calcium release channel function.
Area of Science:
- Cardiology
- Molecular Pharmacology
- Cell Physiology
Background:
- Excitation-contraction (E-C) coupling is crucial for cardiac function.
- L-type Ca channels play a key role in initiating cardiac muscle contraction.
- Dihydropyridine agonists like BAY K 8644 modulate L-type Ca channel activity.
Purpose of the Study:
- To investigate the impact of BAY K 8644 on E-C coupling in ferret ventricular myocytes.
- To determine how BAY K 8644 affects the relationship between L-type Ca current and contraction.
- To elucidate the mechanism by which BAY K 8644 influences calcium-induced calcium release.
Main Methods:
- Isolated ferret ventricular myocytes were used.
- Whole-cell voltage clamp techniques were employed.
- Sarcoplasmic reticulum (SR) Ca load was assessed using caffeine-induced contractures.
- L-type Ca current (ICa) and contraction were measured under varying voltage conditions.
Main Results:
- BAY K 8644 decreased the contraction elicited for a given L-type Ca current and SR Ca load.
- The current-contraction relationship was shifted downward by BAY K 8644.
- A negative shift in the current-voltage relationship of the L-type Ca current was observed.
- Sarcoplasmic reticulum Ca load remained consistent despite BAY K 8644 treatment.
Conclusions:
- BAY K 8644 reduces the efficacy of calcium current to induce SR Ca release during E-C coupling.
- This effect is distinct from BAY K 8644's known enhancement of resting SR Ca release.
- The findings suggest BAY K 8644 may alter the state of the SR Ca release channel via dihydropyridine receptor binding.
Abstract:
We determined the effect of the dihydropyridine L-type Ca channel agonist BAY K 8644 (BAY) on excitation-contraction (E-C) coupling in isolated ferret ventricular myocytes using whole cell voltage clamp. The sarcoplasmic reticulum (SR) Ca load during the test pulses, assessed by caffeine-induced contractures, was similar in the presence and absence of BAY, with extracellular Ca concentration lowered from 3 to 1 mM in BAY. The relationship between L-type Ca current (ICa) and contraction was assessed, with current and contractions measured during depolarizations from -40 to between -30 and +50 mV after a conditioning train (to ensure constant SR Ca load). BAY shifted the current-contraction relationship downward, such that, for a given ICa and SR Ca load, the contraction elicited was much smaller in the presence of BAY. BAY also induced a characteristic negative shift in the the current-voltage relationship. We conclude that BAY decreases the efficacy of a given Ca current to induce SR Ca release during E-C coupling in ferret cardiac tissue (in contrast to the BAY-induced increase of resting SR Ca release). This may reflect an alteration in the state of the SR Ca release channel due to BAY binding to dihydropyridine receptors.