In heart failure, the Na-Ca exchanger is hyperphosphorylated and locked in a highly active state due to reduced levels and activity of associated phosphatases, losing normal muscarinic responsiveness.
Heart failure reduces the level and activity of phosphatases associated with the Na-Ca exchanger, impairing its autonomic regulation and locking it in a highly active state.
BACKGROUND: The Na-Ca exchanger (NCX) is a critical calcium efflux pathway in excitable cells, but little is known regarding its autonomic regulation. METHODS AND RESULTS: We investigated beta-adrenergic receptor and muscarinic receptor regulation of the cardiac NCX in control and heart failure (HF) conditions in atrially paced pigs. NCX current in myocytes from control swine hearts was significantly increased by isoproterenol, and this response was reversed by concurrent muscarinic receptor stimulation with the addition of carbachol, demonstrating "accentuated antagonism." Okadaic acid eliminated the inhibitory effect of carbachol on isoproterenol-stimulated NCX current, indicating that muscarinic receptor regulation operates via protein phosphatase-induced dephosphorylation. However, in myocytes from atrially paced tachycardia-induced HF pigs, the NCX current was significantly larger at baseline but less responsive to isoproterenol compared with controls, whereas carbachol failed to inhibit isoproterenol-stimulated NCX current, and 8-Br-cGMP did not restore muscarinic responsiveness. Protein phosphatase type 1 dialysis significantly reduced NCX current in failing but not control cells, consistent with NCX hyperphosphorylation in HF. Protein phosphatase type 1 levels associated with NCX were significantly depressed in HF pigs compared with control, and total phosphatase activity associated with NCX was significantly decreased. CONCLUSIONS: We conclude that the NCX is autonomically modulated, but HF reduces the level and activity of associated phosphatases; defective dephosphorylation then "locks" the exchanger in a highly active state.
Wei et al. (Tue,) conducted a other in Heart failure. Isoproterenol and carbachol vs. Control swine hearts was evaluated on Na-Ca exchanger (NCX) current and protein phosphatase type 1 levels/activity. In heart failure, the Na-Ca exchanger is hyperphosphorylated and locked in a highly active state due to reduced levels and activity of associated phosphatases, losing normal muscarinic responsiveness.