HEART-RATE AS A DETERMINANT OF L-TYPE CA2- MECHANISMS AND IMPLICATIONIN FORCE-FREQUENCY RELATION( CHANNEL ACTIVITY )

Early studies in enzymatically isolated animal cardiomyocytes indicate d that voltage-gated ''L-type'' Ca2+ currents (I-CaL) can be upregulat ed following an increase of the frequency of activation. Recently, we evidenced a similar regulation of I-CaL in human cardiomyocytes from b oth left and right ventricles and atria over a physiopathological rang e of stimulations (between 0.5 and 5 Hz). This regulation, enhanced by the beta-adrenergic stimulation, may be involved in the frequency-dep endent potentiation of cardiac contractile force in the human healthy myocardium. We show here that the frequency-dependent regulation of I- CaL is controled by the level of phosphorylation, as well as dephospho rylation, of the Ca2+ channels. It was enhanced following activation o f the protein kinase A activated by intracellular cyclic AMP (cAMP). T herefore, we anticipate that all agents stimulating cAMP production wi ll 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 depho sphorylation. Alteration or abnormal modulation by beta-adrenergic rec eptor stimulation of the frequency-dependent facilitation of I-CaL may partly explain the altered force-frequency relation described in hear t failure.