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bioRxiv · 10.1101/2025.11.25.690298

Neuropeptide Y regulation of L-type Ca2+ channel activity is altered following chronic myocardial infarction

Fiore, C. M.·Agarwal, S. R.·Elasoru, S. E.·Ardell, J.·Ajijola, O.·Shivkumar, K.·Harvey, R. D.
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Abstract

Neuropeptide Y (NPY) is a co-transmitter released from sympathetic neurons along with norepinephrine (NE). It has been observed that cardiac NPY levels are significantly elevated following myocardial infarction (MI), and this has been linked to an increase in ventricular arrhythmogenicity associated with elevated sympathetic tone. However, the effects that NPY has on the electrical activity of ventricular myocytes remain poorly understood. Previous studies have examined the influence of NPY alone on cardiac ion channel function, but not in the presence of NE, which is the situation expected in vivo. Furthermore, no one has examined the effects of NPY on ion channel activity following MI. The present study explored the impact of NPY on the L-type Ca2+ current in ventricular myocytes isolated from the hearts of normal healthy pigs and pigs subjected to MI. We found that NPY alone has a stimulatory effect on the Ca2+ current in myocytes isolated from healthy pigs. However, in the presence of NE, the effect of NPY was inhibitory. The stimulatory effect of NPY alone was blocked by the Y1 receptor antagonist BIBO3304, while the inhibitory effect observed in the presence of NE was blocked by the Y2 receptor antagonist BIIE0246. When the effects of NPY were examined using hearts from pigs following recovery from MI, the stimulatory effect of NPY was absent in myocytes obtained from both remote and border zone areas of infarcted hearts. The inhibitory effect of NPY observed in the presence of NE was also absent in myocytes from remote areas of the infarcted heart. However, the inhibitory effect of NPY observed in the presence of NE was intact in border zone cells. The implications of these results are discussed as they relate to the potential arrhythmogenic effects of NPY following MI. Graphical Abstract. NPY exerts bimodular, context dependent effects on LTCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/690298v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@fb248borg.highwire.dtl.DTLVardef@1c3cd9org.highwire.dtl.DTLVardef@1def5b3org.highwire.dtl.DTLVardef@d4bfd5_HPS_FORMAT_FIGEXP M_FIG C_FIG Proposed signaling pathways for diverse effects of NPY in ventricular cardiac myocytes. Norepinephrine (NE) and neuropeptide Y (NPY) co-application results in a Y2/Gi-mediated reduction in {beta}-adrenergic ({beta}AR)/Gs enhanced ICaL, while NPY alone modestly enhances the current via Y1/Gq mechanism. These pathways are regionally altered following chronic MI.

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Fiore, C. M., Agarwal, S. R., Elasoru, S. E., Ardell, J., Ajijola, O., Shivkumar, K., Harvey, R. D.. 2025-11-29. Neuropeptide Y regulation of L-type Ca2+ channel activity is altered following chronic myocardial infarction. https://doi.org/10.1101/2025.11.25.690298

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