S-Bay K8644 is a potent L-type Calcium channel agonist. The positive inotropic effect is a result of increased Calcium Induced Calcium Release (CICR) from the sarcoplasmic reticulum, elicited by elevated cytosolic Calcium concentrations.
Commercially available hiPSC-derived cardiomyocytes show EC50 values of approximately 10 nM, indicating intact Calcium handling in those cell models. The contraction amplitude increases up to approx. 150% in standard maintenance medium supplied by cell manufacturers.
In contrast to isoproterenol, S-Bay K8644 induces significant alterations of the symmetry of the contraction-relaxation-cycle. While the contraction phase is slightly shortened (increased acceleration), the relaxation phase is considerably prolonged due to increased cytosolic Calcium concentrations.
As a result from the shortening of the contraction phase in combination with the increase in contraction amplitude, the upstroke slope is significantly increased at concentrations above 10 nM . At the same time, the prolongation of the relaxation phase results in a decreased slope of this phase.