The long term objectives of this application is the investigation of the mechanism by which cardiac steroids modify the electrical and mechancial events of the cardiac tissues.
The specific aims i nclude (1) an evaluation of the mechansisms by which cardiac steroids increase cellualr sodium; (2) the role of cellular sodium level in force development; (3) the relationship between intracellular sodium and the oscillatory potential; (4) the mechanism of abolition of the oscillatory potential; (5) the relative importance of sodium and calcium in cardiac steroid inotropy; (6) the mechanism of the reversal of calcium overload; (7) the analysis of the action of cardiac steroid in the sinus node (8) the mode of action of therapeutic interventions. The experiments will be conducted in isolated perfused tissues. The transmembrane potentials will be recorded with a microelectrode technique together with the twitch. The intracellular sodium activity will be measured with a Na-selective microelectrode. Voltage clamp method will involve the use of two microelectordes in short sigments of Purkinje fibers. The tissues to be investigated include ventricular Purkinje fibers, atrial and ventricular muscle fibers, and the sinus node. The experiments will involve changes in external ionic environment, selective blockage of cardiac currents, changes in transmembrane fluxes of sodium and calcium and the analysis of the dependance of some phenomena on voltage. Both low (""""""""therapeutic"""""""") and high (toxic) concentrations of cardiac glycosides will be used in an effort to determine whether the mechanism of the inotropic effect is the same. The changes in electrical activity, mechanical activity and aiNa will be correlated. The different techniques should permit the identification of the factors of importance in the positive inotropic effect of cardiac steroids and in the electrical and mechanical toxicity induced by high concentrations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL017451-16
Application #
3335364
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1977-09-01
Project End
1991-12-31
Budget Start
1989-09-01
Budget End
1991-12-31
Support Year
16
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Gonzalez, M D; Vassalle, M (1993) Role of oscillatory potential and pacemaker shifts in digitalis intoxication of the sinoatrial node. Circulation 87:1705-14
Abete, P; Vassalle, M (1992) Role of intracellular Na+ activity in the negative inotropy of strophanthidin in cardiac Purkinje fibers. Eur J Pharmacol 211:399-409
Vassalle, M; Kotake, H; Lin, C I (1992) Pacemaker current, membrane resistance, and K+ in sheep cardiac Purkinje fibres. Cardiovasc Res 26:383-91
Aceto, E; Vassalle, M (1991) On the mechanism of the positive inotropy of low concentrations of strophanthidin. J Pharmacol Exp Ther 259:182-9
Aceto, E; Vassalle, M (1991) On the antiarrhythmic mechanisms of magnesium in cardiac Purkinje fibers. Magnes Trace Elem 10:355-63
Abete, P; Ferrara, N; Rengo, F et al. (1991) Mechanisms of lidocaine actions on normal and abnormal rhythms in canine cardiac tissues in vivo and in vitro. Clin Exp Pharmacol Physiol 18:179-91
Tamargo, J; Vassalle, M (1991) Mechanisms by which calcium modulates diastolic depolarization in sheep cardiac Purkinje fibers. J Electrocardiol 24:349-61
Iacono, G; Vassalle, M (1990) On the mechanism of the different sensitivity of Purkinje and myocardial fibers to strophanthidin. J Pharmacol Exp Ther 253:1-12
Aceto, E; Vassalle, M (1990) Magnesium and intracellular sodium activity in cardiac Purkinje fibers. Magnes Trace Elem 9:152-62
Iacono, G; Vassalle, M (1990) The interrelationship of cesium, intracellular sodium activity, and pacemaker potential in cardiac Purkinje fibers. Can J Physiol Pharmacol 68:1236-46

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