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Directionality in drug action on sodium-calcium exchange.
1Department of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Denis.noble@physiol.ox.ac.uk
Annals of the New York Academy of Sciences
|April 21, 2007
Summary
Drugs inhibiting calcium entry into cells via exchangers may seem beneficial but are thermodynamically impossible. Their apparent effectiveness depends on operating conditions, not inherent drug properties.
Area of Science:
- Physiology
- Biochemistry
- Pharmacology
Background:
- Pathological conditions can lead to detrimental calcium influx through cellular exchangers.
- Developing drugs to inhibit calcium entry while preserving calcium efflux is a therapeutic goal.
Purpose of the Study:
- To investigate the thermodynamic feasibility of drugs inhibiting cellular calcium entry via exchangers.
- To understand the apparent differential effectiveness of such inhibitors under various conditions.
Main Methods:
- Thermodynamic analysis of exchanger function.
- Assessment of drug action under conditions favoring net calcium entry versus calcium exit.
- Evaluation of sodium dependence on drug efficacy.
Main Results:
- Thermodynamically, drugs cannot inhibit calcium entry while allowing calcium exit.
- Apparent differences in inhibitor effectiveness are due to varying experimental conditions.
- Drug action is strongly dependent on internal sodium concentrations.
- Near equilibrium, drug efficacy is consistent for both calcium entry and exit modes.
Conclusions:
- The concept of a drug selectively inhibiting calcium entry via exchangers is thermodynamically unachievable.
- Observed variations in drug effectiveness are artifacts of experimental conditions and sodium dependence.
- Understanding these thermodynamic and kinetic factors is crucial for developing effective exchanger modulators.
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