Mechanisms of enhanced phosphorylase activation in the hyperthyroid rat heart

Enhanced phosphorylase activation in hearts from hyperthyroid animals has been well documented. To elucidate the mechanisms responsible for the enhanced phosphorylase a formation, hearts from euthyroid and hyperthyroid rats were perfused by the Langendorff method with calcium (3.75 mM), isoproterenol, dibutryl cAMP and trifluoperazine, an inhibitor of calcium-calmodulin dependent enzymes. Comparative biochemical analyses revealed increased phosphorylase a formation in hearts from both euthyroid and hyperthyroid animals following exposure to calcium, dibutryl cAMP and isoproterenol. Hearts from hyperthyroid rats had an increased sensitivity to threshold concentrations of isoproterenol for both cAMP formation and phosphorylase b to a conversion. At higher concentrations of isoproterenol (10(-8) M and 3 x 10(-8) M), no significant differences in cAMP formation were noted between euthyroid and hyperthyroid animals in spite of persistently increased phosphorylase a levels in the hyperthyroid state. Trifluroperazine had no effect on basal phosphorylase a levels but significantly inhibited phosphorylase a formation in both groups following calcium or isoproterenol stimulation. However, enhanced phosphorylase a formation was still present in the hearts from hyperthyroid rats following trifluoperazine preperfusion. Determinations of phosphorylase kinase activity revealed a specific activity in the hyperthyroid animals twice that of the euthyroid controls. At least two mechanisms, an increased sensitivity to beta-adrenergic agents and increased cardiac phosphorylase kinase activity, may mediate the enhanced phosphorylase a formation found in hearts from hyperthyroid rats.