Post-β-receptor impairment in the regulation of myofibrillar Ca²⁺ sensitivity in tachypacing-induced canine failing heart

Although one of the salient abnormalities in signal transduction of failing myocardium is downregulation of the β-adrenergic receptor, the extent of presentation of downstream pathways distal to β-receptors is misunderstood. We addressed this question in tachypacing-induced canine failing heart by assessing changes in myofibrillar Ca²⁺ sensitivity and troponin I phosphorylation. At a basal state, no significant difference in myofibrillar Ca²⁺ sensitivity was found between normal and failing hearts. Isoproterenol 8-bromo-cylic adenosine monophosphate (cAMP), and 8-bromo-cAMP isobutylmethylxantine all significantly decreased the Ca²⁺ sensitivity in the normal, but not in the failing, heart. EMD57033 (10 μM), a myofibrillar Ca²⁺ sensitizer increased the Ca²⁺ sensitivity to a similar extent in both groups. The troponin I phosphorylation levels were significantly decreased in the failing heart. These results suggest that abnormalities of the β-adrenergic signaling system exist not only at the receptor level but also at downstream steps after cAMP production.