Contribution of frequency-augmented inward Ca²⁺ current to myocardial contractility

The sarcoplasmic reticular Ca²⁺ pump (SERCA) is thought to be the primary determinant of heart rate-dependent increases in myocardial contractile [Ca²⁺]_i and force (force-frequency relationship (FFR)), an important mechanism to increase cardiac output. This report demonstrates a rate-dependent role for inward Ca²⁺ current (I_ca) in the human and rat FFR. Human action potential plateau height increased linearly with contractility when heart rate increased in vivo, as measured by monophasic action potential catheter and echocardiography. Rat rate-dependent developed force and cytosolic [Ca²⁺]_i transients were quantified in isolated left ventricular papillary muscles, and Ica and action potential duration in car- diomyocytes. I_ca and SERCA measurements better reflected [Ca²⁺]_i and force transients than SERCA activity alone. These data support a direct and (or) indirect contribution to myocardial contractility by I_ca at heart rates from approximately 1 to 3-4 Hz (60 to 180-240 bpm) in tandem with SERCA to sustain the typical 'bell shape' of the FFR across species.