Altered phosphorylation of sarcoplasmic reticulum contributes to the diminished contractile response to isoproterenol in hypertrophied rat hearts

We tested the hypothesis that changes in phosphorylation of the sarcoplasmi c reticulum (SR) protein, phospholamban (PIB) and myofibrillar proteins tro ponin I (TnI) and C protein are responsible for the decreased relaxant resp onse to isoproterenol in cardiac hypertrophy and failure induced by ascendi ng aortic banding in rats. In isolated perfused heart preparations under ma ximal isoproterenol stimulation, the capacity for in vitro cAMP-dependent p hosphorylation of PIB was significantly increased at the compensatory stage of hypertrophy (126-130%, P<0.001), but decreased with failure (70-76%, P< 0.001). Phosphorylation of TnI also decreased in the failing hearts, howeve r to a lesser extent (80-83%, P<0.05). No significant hypertrophy-related d ifference was evident in isoproterenol-induced phosphorylation of C protein . The relative tissue level of PIB was increased (150-168%, P<0.001) in hyp ertrophied and decreased (71-83.8%, P<0.05) in failing hearts compared with the respective age-matched sham-operated controls (100%). As a percentage above baseline, the maximal isoproterenol-induced increase in the EC,, of t he SR Ca2+ pump in response to phosphorylation of PIB was 38.5+/-1.1% for s ham-operated rats, and 26.0+/-3.8% and 15.4+/-4.2% for hypertrophied and fa iling hearts respectively. As a consequence, linear correlation was observe d between the maximal increase in EC50 and the maximal rate of relaxation [ (-dP/dt)/DevP] upon isoproterenol stimulation, declining with progressive h ypertrophy to failure. These data suggest that hypertrophy-induced alterati ons in PIE phosphorylation and protein level contribute to the diminished r elaxant response of the hypertrophied and failing heart to adrenergic agoni sts.