Abstract

The objectives of the present investigation are: (1) To further test the modulated receptor hypothesis for the action of antiarrhythmic drugs on cardiac sodium channels. (2) To develop a faster and more complete search method for analysis of the experimental results, including upper and lower limits for the estimates. (3) To characterize the structure-activity relationship for lidocaine procainamide, aprindine and amiodarone derivatives. (4) To continue the development of a preparation that can be voltage clamped. (5) To study drug interactions in terms of modulated receptor hypothesis. It is hoped that this research will further improve our understanding of the action of antiarrhythmic drugs; that the elucidation of the QSAR will promote the development of better and safer antiarrhythmic drugs; that the drug interactions will provide better use of the currently available drugs. Guinea pig papillary muscles and single isolated cardiocytes will be voltage clamped. The sodium current or Vmax will be measured and these data will be used to estimate the drug blocked channels. By clamping the preparations to various potentials and different durations it is possible to determine the affinity and the kinetics of the interaction of antiarrhythmic drugs with sodium channels. The modulated receptor constants and the biophysical properties of the drugs will be correlated using cluster analysis techniques to unravel the structure activity relationship in a quantitative fashion (QSAR). The results of QSAR will be used to improve existing antiarrhythmic drugs and to design new ones.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036020-02
Application #
3350504
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-07-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203

  Publications

Murray, K T; Anno, T; Bennett, P B et al. (1990) Voltage clamp of the cardiac sodium current at 37 degrees C in physiologic solutions. Biophys J 57:607-13
Anno, T; Hondeghem, L M (1990) Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery. Circ Res 66:789-803
Snyders, D J; Hondeghem, L M (1990) Effects of quinidine on the sodium current of guinea pig ventricular myocytes. Evidence for a drug-associated rested state with altered kinetics. Circ Res 66:565-79
Stewart, S J; Prpic, V; Johns, J A et al. (1989) Bacterial toxins affect early events of T lymphocyte activation. J Clin Invest 83:234-42
Johns, J A; Anno, T; Bennett, P B et al. (1989) Temperature and voltage dependence of sodium channel blocking and unblocking by O-demethyl encainide in isolated guinea pig myocytes. J Cardiovasc Pharmacol 13:826-35
Bennett, P B; Kass, R; Begenisich, T (1989) Nonstationary fluctuation analysis of the delayed rectifier K channel in cardiac Purkinje fibers. Actions of norepinephrine on single-channel current. Biophys J 55:731-8
Bennett, P B; Woosley, R L; Hondeghem, L M (1988) Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels. Circulation 78:692-700
Roden, D M; Bennett, P B; Snyders, D J et al. (1988) Quinidine delays IK activation in guinea pig ventricular myocytes. Circ Res 62:1055-8
MeLean, M J; Bennett, P B; Thomas, R M (1988) Subtypes of dorsal root ganglion neurons based on different inward currents as measured by whole-cell voltage clamp. Mol Cell Biochem 80:95-107
Ehring, G R; Moyer, J W; Hondeghem, L M (1988) Quantitative structure activity studies of antiarrhythmic properties in a series of lidocaine and procainamide derivatives. J Pharmacol Exp Ther 244:479-92

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