Phospholamban: A major determinant of the cardiac force-frequency relationship

Bluhm W.F., Kranias E.G., Dillmann W.H., and Meyer M.

The cardiac force-frequency relationship has been known for over a century, yet its mechanisms have eluded thorough understanding. We investigated the hypothesis that phospholamban, a potent regulator of the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), determines the cardiac force-frequency relationship. Isolated left ventricular papillary muscles from wild-type (WT) and phospholamban knock-out (KO) mice were stimulated at 2 to 6 Hz. The force-frequency relationship was positive in WT, but negative in KO muscles, i.e., it was inverted by ablation of phospholamban (p<0.01, n=6). From 2 to 6 Hz, relaxation accelerated considerably (by 10 ms) in WT muscles, but only minimally (by 2 ms) in KO muscles (WT vs. KO: p<0.0001, n=6). In order to show that the lack of frequency potentiation in KO muscles was not explained by the almost maximal basal contractility, twitch duration was prolonged in six KO muscles with the SERCA inhibitor cyclopiazonic acid to WT values. Relaxation still failed to accelerate with increased frequency. In conclusion, our results clearly identify phospholamban as a major determinant of the cardiac force-frequency relationship.