Heart rate as a determinant of L-type Ca²⁺ channel activity: Mechanisms and implication in force-frequency relation

Abstract

Early studies in enzymatically isolated animal cardiomyocytes indicated the voltage-gated “L-type” Ca²⁺ currents (I_CaL) can be upregulated following an increase of the frequency of activation. Recently, we evidenced a similar regulation of I_CaL in human cardiomyocytes from both left and right ventricles and atria over a physiopathological range of stimulations (between 0.5 and 5 Hz). This regulation, enhanced by the β-adrenergic stimulation, may be involved in the frequency-dependent potentiation of cardiac contractile force in the human healthy myocardium. We show here that the frequency-dependent regulation of I_CaL is controlled by the level of phosphorylation, as well as dephosphorylation, of the Ca²⁺ channels. It was enhanced following activation of the protein kinase A activated by intracellular cyclic AMP (cAMP). Therefore, we anticipate that all agents stimulating cAMP production will favor this process, which was demonstrated here by activating 5HT-4 receptors using serotonin. Alternatively, it was also enhanced by the phosphatase inhibitor okadaic acid which prevents Ca²⁺ channels dephosphorylation. Alteration or abnormal modulation by β-adrenergic receptor stimulation of the frequency-dependent facilitation of I_CaL may partly explain the altered force-frequency relation described in heart failure.