| Autor: |
Baine, Stephen H, Belevych, Andriy, Bonilla, Ingrid M, Carnes, Cynthia A, Gyorke, Sandor |
| Zdroj: |
Circulation (Ovid); November 2019, Vol. 140 Issue: Supplement 1 pA15725-A15725, 1p |
| Abstrakt: |
Heart Failure (HF) is characterized by autonomic imbalance associated with increased sympathetic output with a concomitant decrease in parasympathetic outflow which is thought to contribute to disease progression. While the sympathetic nervous system has received considerable attention, the parasympathetic nervous system and its role in HF has largely been underexplored. An FDA approved acetylcholinesterase inhibitor, pyridostigmine, has been shown to improve cardiac hemodynamics clinically and ventricular function experimentally. Here we propose a novel mechanism by which pyridostigmine improves cardiac function in HF via enhancement of myocyte calcium handling. We employed a transverse aortic constriction (TAC) model of HF in C57BL6/J mice to investigate the role of chronic pyridostigmine treatment in failing hearts. Chronic treatment with 2-10mg/kg/day for 28 days with pyridostigmine (osmotic pump) resulted in 40-60% inhibition of plasma acetylcholinesterase activity. Pyridostigmine attenuated TAC-induced decreases in ejection fraction and fractional shortening. Next, we employed confocal microscopy using calcium sensitive Fluo-3 dye to examine calcium handling in diseased myocytes. During acute isoproterenol treatment, TAC myocytes exhibited increased calcium wave frequency and decreased calcium transient amplitude, while pyridostigmine treatment significantly reduced calcium wave frequency vs. TAC and significantly increased transient amplitude (1Hz). To evaluate the molecular mechanisms contributing to improvements in calcium handling, we performed Western blot for phosphorylation of the critical calcium release channel; the ryanodine receptor (RyR2). In TAC myocytes, we observed a significant increase in RyR2 Ser-2814 phosphorylation vs. WT sham myocytes, which was attenuated by pyridostigmine. Overall, our studies indicate a novel mechanism by which chronic pyridostigmine treatment attenuates sympathetically-mediated abnormalities in calcium handling, both in vivo and ex vivo. Improved autonomic balance may improve aberrant calcium handling and attenuate arrhythmias and contractile dysfunction in HF. |
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