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Evidence for an interaction of halothane with the L-type Ca2+ channel in human myocardium
U Schmidt1, R H Schwinger, S Böhm
1Medizinische Klinik I, Universität München, Germany.
Insights
Halothane, an anesthetic, interacts with L-type calcium channels in human heart muscle, affecting its contractility. This interaction with dihydropyridine binding sites may explain halothane's cardiac depressant effects.
Area of Science:
- Cardiology
- Anesthesiology
- Pharmacology
Background:
- Investigating mechanisms of halothane's cardiac depressant effects.
- Hypothesizing an interaction between halothane and L-type Ca2+ channels in human myocardium.
- Examining functional consequences for myocardial force generation.
Purpose of the Study:
- To determine if halothane interacts with L-type Ca2+ channels in human myocardium.
- To assess the functional impact of this interaction on myocardial contractility.
Main Methods:
- Experiments on isolated, electrically driven human ventricular preparations and cardiac membranes.
- Radioligand binding assays using 3H-PN 200-110.
- Myocardium obtained from human failing and non-failing hearts during surgery.
Main Results:
- Halothane induced a negative inotropic effect in both non-failing and failing myocardium.
- Halothane reduced the binding of 3H-PN 200-110 to cardiac membranes in a concentration-dependent manner.
- Halothane shifted concentration-response curves for L-type Ca2+ channel agonist BayK 8644, indicating channel interaction.
Conclusions:
- Halothane interacts with L-type Ca2+ channels in human ventricular myocardium by affecting dihydropyridine binding sites.
- This interaction partially explains halothane's negative inotropic effect.
- The findings suggest a potential general role in halothane's anesthetic properties.
Background:
The present study was aimed at investigating the underlying mechanisms for the cardiac depressant effect of halothane. To test the hypothesis, whether there is an interaction of halothane with the L-type Ca2+ channels in human myocardium and whether this interaction has functional consequences for force generation in the human myocardium, effects of halothane were studied in human myocardial membranes and isolated cardiac preparations.
Methods:
The experiments were performed on isolated, electrically driven ventricular preparations (1 Hz, 37 degrees C) and cardiac membranes with radioligand binding experiments using 3H-PN 200-110. Myocardium from human failing and non-failing hearts was obtained at cardiac surgery.
Results:
Halothane produced a negative inotropic effect, which was similar in nonfailing and failing myocardium. Halothane shifted the concentration-response curve for the positive inotropic effect of the L-type Ca2+ channel agonist BayK 8644 to the right. The density of dihydropyridine receptors as judged from 3H-PN 200-110 radioligand binding experiments was similar in nonfailing and failing myocardium, whereas the density of beta-adrenoceptors was reduced. Halothane concentration dependently reduced the binding of 3H-PN 200-110, an antagonist at the 1,4 dihydropyridine receptor site of the Ca2+ channel, to myocardial membranes. Furthermore, halothane produced a rightward shift of the competition curve of BayK 8644 for binding of 3H-PN 200-110 to cardiac membranes.
Conclusions:
In human ventricular myocardium, halothane exhibits an interaction with the L-type Ca2+ channel by interfering with its dihydropyridine binding sites. This may explain, at least in part, the observed negative inotropic effect of this agent and could hypothetically play a general role in its anesthetic effects.