Modulation of force-frequency relation by phospholamban in genetically engineered mice

Vivek J. Kadambi, Nancy Ball, Evangelia G. Kranias, Richard A. Walsh, Brian D. Hoit
1999 American Journal of Physiology. Heart and Circulatory Physiology  
Modulation of force-frequency relation by phospholamban in genetically engineered mice. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H2245-H2250, 1999.-Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca 2ϩ 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
more » ... (PLBKO), and isogenic wild-type controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (ϩdP/dt max ), and diastolic function was assessed by both the peak rate (ϪdP/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. ϪdP/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 ϩdP/dt max increased in both PLBKO and PLBOE compared with their isogenic controls (both P Ͻ 0.05). The HR crit for LV ϩdP/dt max was significantly higher in PLBKO (427 Ϯ 20 beats/min) compared with controls (360 Ϯ 18 beats/min), whereas the HR crit in PLBOE (340 Ϯ 30 beats/min) was significantly lower compared with that in isogenic controls (440 Ϯ 25 beats/min). The intrinsic heart rates were significantly lower, and the HR crit and the ϮdP/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 The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
doi:10.1152/ajpheart.1999.276.6.h2245 fatcat:dd5fcd2drrdmzjc4shfck4qheq