Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca²⁺ pump activity and myocardial contractility. To determine whether and to what extent phospholamban modulates the force-frequency relation and ventricular relaxation in vivo, we studied transgenic mice overexpressing phospholamban (PLBOE), gene-targeted mice without phospholamban (PLBKO), and isogenic wild-type controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (+dP/dt_max), and diastolic function was assessed by both the peak rate (dP/dt_max) and the time constant () of isovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atrial pacing was used to generate heart rate vs. dP/dt_max (force-frequency) relations. Biphasic force-frequency relations were produced in all animals, and the critical heart rate (HR_crit) was taken as the heart rate at which dP/dt_max was maximal. The average LV +dP/dt_max increased in both PLBKO and PLBOE compared with their isogenic controls (both P < 0.05). The HR_crit for LV +dP/dt_max was significantly higher in PLBKO (427 ± 20 beats/min) compared with controls (360 ± 18 beats/min), whereas the HR_crit in PLBOE (340 ± 30 beats/min) was significantly lower compared with that in isogenic controls (440 ± 25 beats/min). The intrinsic heart rates were significantly lower, and the HR_crit and the ±dP/dt_max at HR_crit were significantly greater in FVB/N than in SvJ control mice. We conclude that 1) the level of phospholamban is a critical negative determinant of the force-frequency relation and myocardial contractility in vivo, and 2) contractile parameters may differ significantly between strains of normal mice.

treppe; myocardial contractility; hemodynamics

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