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Negative lusitropic effect of DPI 201-106 and E4031. Possible role of prolonging action potential duration
H E Cingolani1, R T Wiedmann, J J Lynch
1Merck Sharp and Dohme Research Laboratories, West Point, PA.
Insights
Both E4031 and DPI 201-106 (DPI) prolonged cardiac action potential duration and refractory period, leading to slowed relaxation. This suggests a link between action potential prolongation and negative lusitropic effects.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Class III antiarrhythmic agents and cardiotonic agents can affect cardiac electrophysiology.
- Understanding the mechanisms of drug-induced changes in cardiac function is crucial for patient safety and therapeutic development.
Purpose of the Study:
- To investigate the in vivo and in vitro effects of E4031 and DPI 201-106 (DPI) on left ventricular pressure decay and contractility.
- To explore a potential causal link between action potential duration (APD) prolongation and negative lusitropic effects induced by these drugs.
Main Methods:
- In vivo studies in anesthetized dogs measuring left ventricular pressure decay and contractility parameters.
- In vitro studies using isometrically contracting rabbit papillary muscles to assess developed tension and relaxation dynamics.
- Measurement of effective refractory period in papillary muscles.
Main Results:
- Both E4031 and DPI increased the time constant of left ventricular pressure decay, indicating slowed relaxation.
- These drugs prolonged cardiac refractoriness and action potential duration (APD) in vivo and in vitro.
- Negative lusitropic effects were observed with E4031 and DPI, but not when contractility was increased by extracellular Ca2+.
Conclusions:
- A causal link is postulated between the prolongation of action potential duration (APD) and the negative lusitropic effects of E4031 and DPI.
- These findings highlight the complex interplay between electrophysiological changes and mechanical function in the heart.
- Further research is warranted to elucidate the precise molecular mechanisms involved.
Abstract:
In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.