Modulation of the force frequency relation in human atrial myocardium by ivabradine and calmodulin antagonists?

• Published in: The Thoracic and Cardiovascular Surgeon
• Main Authors: Karliova, I, Denk, K, Balota, S, Kayhan, N, Peivandi, AA, Vahl, CF
• Format: Conference Proceeding
• Language: English
• Published: 01.02.2010
• ISSN: 0171-6425; 1439-1902
• DOI: 10.1055/s-0029-1246789

Objective: The force frequency relation (FFR) is an important intrinsic regulatory mechanism of cardiac contractility and governed by modulation of intracellular Calcium transient. The present analysis focuses on modulations of the FFR due to pharmacological agents with an action aside from the Sarcoplasmic reticulum and Calcium channels. Methods: The Calmodulinantagonists Trifluoperazine and Chlorpromacine and the „fancy channel modulator“ Ivabradin were used in maximum therapeutucal concentrations while isolated human trabeculae (n=8) were subjected to different stimulation frequencies (30, 60, 90, 120 beats per minute). Resting tension and active tension were recorded as a function of stimulation frequencies. (Measurement conditions: 37°C, Krebs-Henseleit solution, supramaximal electrical stimulation, frequency: 1Hz). Control measurements were performed in any series. Results: The FFR relation was well preserved (force elevation with increasing stimulation frequency) when any of the substances was added. Trifluoperazine and Chlorpromazine hat no significant acute effect on isometric force, but significantly retarded the velocity of relaxation at 90 and 120 peats per minute (Trifluoperazine p<0.001, Chlorpromazine p<0.05). In contrast ivabradin was associated with an increase of active isometric force generation and a decrease of passive resting tension. Conclusion: Although the primary cellular mechanism responsible for the FFR is determined by the sarcoplasmic reticulum calcium load and calcium flux through the sarcolemma, the present data suggest, that Calmodulin contributes to a positive FFR and the frequency dependent acceleration of relaxation. Ivabradine has – aside from the fancy channel – a direct positive inotropic effect in human myocardium aside from the sarcoplasmic reticulum.