The contractile response measured as maximum rate of force development to a near threshold concentration of isoproterenol (1 nM) was enhanced in perfused interventricular septa from hyperthyroid (128±4% control) compared with euthyroid rats (105±2%, P < 0.01). This enhanced contractile response was accompanied by a significant activation of cyclic (c)AMP-dependent protein kinase (protein kinase activity ratio increased from 0.159±0.008 to 0.218±0.019, P < 0.005, although no significant changes from base line occurred in euthyroid septa, 0.152±0.007-0.179±0.012). No difference between hyperthyroid and euthyroid hearts was observed in the contractile response to 0.1 mM dibutyryl cAMP (126.5±2.5% and 122.0±9.2% in hyperthyroid and euthyroid, respectively), and the magnitude of the response to dibutyryl cAMP was comparable with that observed in the hyperthyroid group with 1 nM isoproterenol. These results suggest that the mechanism for enhanced protein kinase activation and contractile response to low concentrations of isoproterenol in the hyperthyroid heart is at or proximal to cAMP generation. The maximum contractile response to isoproterenol (0.5 μM), however, was decreased in hyperthyroid myocardium (192±13%) compared with euthyroid (291±37%, P < 0.05). Both protein kinase activity ratio (0.356±0.017 and 0.344±0.013) and the maximum contractile response to Ca++ (335±15 and 340±12% control in hyperthyroid and euthyroid, respectively) were similar, suggesting that the mechanism of the diminished maximum response was distal to protein kinase activation but not a function of an altered Ca++-troponin interaction. The diminished maximum rate of force development response in the hyperthyroid hearts was accompanied by significantly less shortening of the contraction duration that was 85.6±2.1% control in hyperthyroid vs. 66±2.8% control in euthyroid, P < 0.001. Although the basal rate of Ca++ accumulation was greater in microsomes isolated from hyperthyroid than from euthyroid hearts, there was significantly less additional stimulation of Ca++ accumulation in response to exogenous cAMP and protein kinase in hyperthyroid compared with euthyroid hearts. This reduction may explain the diminished effect of isoproterenol on the shortening of contraction duration in hyperthyroid compared with the euthyroid myocardium, and may explain, at least in part, the diminished maximum contractile response to isoproterenol.
Thomas Guarnieri, Charles R. Filburn, Elsie S. Beard, Edward G. Lakatta
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