REGULATORY EFFECTS OF PHOSPHOLAMBAN ON CARDIAC-FUNCTION IN INTACT MICE

Phospholamban (PLB) regulates Ca2+-adenosinetriphosphatase activity in cardiac sarcoplasmic reticulum and participates in the regulation of myocardial performance. Animal models with altered levels of PLB permi t in vivo evaluation of the physiological role of PLB. This study exam ined left ventricular (LV) performance in intact PLB heterozygous and homozygous mice under basal and stimulated conditions. A Millar Mikro- Tip transducer was inserted into the right carotid artery and advanced into the LV for direct measurement of ventricular pressure and the fi rst derivative of intraventricular pressure (dP/dt). Baseline blood pr essures were increased in PLB heterozygotes and even more so in PLB ho mozygotes compared with wild types (WT), and there were no differences in heart rate or LV end-diastolic pressure. The increase in pressure was primarily caused by an increase in systolic pressure. Baseline val ues for positive and negative dP/dt were linearly correlated with PLB levels. In PLB heterozygotes, contractile response to isoproterenol (I so) was blunted compared with WT, but maximum rates of contraction wer e similar between the two groups. Contractile performance in PLB homoz ygous mice, which under baseline conditions was similar to maximum lev els seen in WT, showed a blunted response to Iso, and maximum rates of contraction were significantly greater than in either of the other gr oups, indicating an essential but perhaps not exclusive role for PLB i n mediating the inotropic effects of beta-adrenergic agonists. The eff ects of Iso on negative dP/dt were also blunted in both PLB heterozygo us and PLB homozygous animals. Our results demonstrate that myocardial function is highly dependent on PLB level and suggest that the cardio vascular effects of PLB perturbations are largely uncompensated for in the intact mouse.