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Halothane decreases actomyosin ATPase activity: a possible mechanism of the negative inotropic effect
Insights
Halothane, an inhalation anesthetic, depresses cardiac muscle function by inhibiting ATP utilization in the contractile system. This dose-dependent effect reduces cardiac actomyosin ATPase activity, potentially explaining myocardial depression.
Area of Science:
- Cardiology
- Anesthesiology
- Biochemistry
Background:
- Inhalation anesthetics like halothane cause dose-dependent cardiac muscle depression.
- The precise mechanism of halothane's negative inotropic effect remains unclear.
- Previous studies on halothane's impact on contractile protein ATPase had methodological limitations.
Purpose of the Study:
- To investigate the effect of halothane on canine cardiac natural actomyosin ATPase activity.
- To determine if inhibition of ATP utilization by the contractile system contributes to halothane-induced myocardial depression.
Main Methods:
- Measured ATP splitting by canine cardiac natural actomyosin.
- Utilized established extraction and equilibration procedures.
- Calculated drug dosing based on halothane's partition coefficient in protein.
Main Results:
- Halothane shifted the Ca++ concentration-effect curve for actomyosin ATPase activity to the right.
- The maximum depression of ATPase activity was observed at pCa 7.0 or 6.5.
- The inhibitory effect was dose-dependent, reversible, and antagonized by high Ca++ concentrations.
Conclusions:
- Halothane inhibits ATP utilization by the cardiac contractile system.
- This inhibition of actomyosin ATPase activity is a potential mechanism for halothane's in vivo myocardial depression.
Abstract:
Like all inhalation anesthetics, halothane (CF3CHBrCl) has a dose-dependent negative inotropic effect on cardiac muscle. The mechanism of the action has not been determined, although effects on glycolysis, mitochondrial respiration and calcium kinetics, and sarcoplasmic reticulum ATPase activity have been suggested. Previous studies of the effect of halothane on the ATPase of contractile protein suffered from design and dosing defects. We have measured ATP splitting by canine cardiac natural actomyosin using extraction and equilibration procedures described previously (Honig, C. R. and Reddy, Y. C. 1973, J. Pharmacol. 184: 330-338). Drug dosing calculations were facilitated by measurement of the partition coefficient of halothane in protein. Halothane shifted the Ca++ concentration effect curve for actomyosin ATPase activity to the right. The maximum depression occurred at pCa 7.0 or 6.5. The effect was dose dependent with less than 10 percent depression at threshold and 50-60 percent depression at peak. Enzyme inhibition was antagonized by high Ca++ concentration, and was reversed by removing halothane from the reaction mixture. We suggest that inhibition of ATP utilization by the contractile system may be a mechanism of the in vivo myocardial depression produced by halothane.