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

Abstract

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 (ICa) 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 cardiomyocytes. ICa 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 ICa 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.

Adrenergic effects on force-frequency relationship: a pivotal role for the cardiac intrinsic systems

“…Moreover, it is well known that b-adrenergic stimulation contributes significantly to contractile proteins phosphorylation (Kranias & Solaro 1982). Thus it is probable that under our experimental condition, in agreement also with in vitro studies, the frequency-dependent facilitation of increased intra-myocytes Ca 2+ transient plays a primary role: the start of heart pacing quickly increases inward calcium current (I Ca ) sufficient to increase Ca 2+ dependent -Ca 2+ release from SR, supplying on the one hand more Ca 2+ to rate-sensitized contractile machinery improving contractility and, on the other hand, a further stimulation of SERCA 2 activity (Parilak et al 2009) and myoproteins phosphorylation, improving relaxation (Tong et al 2004, Varian & Janssen 2007. These molecular events could produce the sympatholytic insensitive phase (first phase).…”

“…Thus, neurohumoral ß-adrenergic activation, such as during stress or intense exercise, added to the effects of HR increase, plays a primary role in contractility modulation also by amplifying the F-FR (Epstein et al 1965, Ross 1998, De Pauw et al 2004). The underlying cellular mechanisms of the F-FR are described and shown to be related to rate-dependent changes in Ca 2+ availability and movements within the myocardial cells (Allen & Blinks 1978, Sipido et al 1998, Reuter et al 1999, Parilak et al 2009). In addition, experimental evidence suggests that the myofilament Ca 2+ sensitivity is frequency dependent (Tong et al 2004).…”

The heart in Duchenne muscular dystrophy: early detection of contractile performance alteration

“…Force production usually declines at higher stimulation frequencies, i.e . a negative ‘treppe’ in wt mouse papillary-like muscle from 8 Hz stimulation or in rat papillary muscle already at <6 Hz 24 . However, as stated by Redel et al .…”

Comparison of contractile behavior of native murine ventricular tissue and cardiomyocytes derived from embryonic or induced pluripotent stem cells

“…This phenomenon, termed positive FFR, serves to increase cardiac output during exercise or stress conditions (25). The mechanisms underlying FFR have been thoroughly investigated (25), and it is commonly thought that the positive FFR relation results from augmented SR [Ca 2+ ] release at higher rates and perhaps a rate‐dependent increase of the inward Ca 2+ current (26). During positive FFR, SR Ca 2+ content, [Ca 2+ ] i transient amplitude, and phosphorylation of phospholamban (27) increase, whereas during negative FFR, the reverse situation is likely to occur.…”