Spinal neuromodulation by intrathecal oxytocin administration mitigates the myocardial ischemia induced sympathoexcitation by suppressing the ischemia-related spinal neural hyperactivity

Abstract

Background: Myocardial ischemia can lead to fatal ventricular arrhythmias by disrupting the cardiospinal neural network which controls the sympathoexcitation. Spinal neuromodulation techniques could decrease myocardial ischemia-induced sympathoexcitation by modulating the spinal neural network. Hypothesis: We hypothesize that spinal oxytocin (OXT) administration decreases myocardial ischemia-induced sympathoexcitation by suppressing spinal neural hyperactivity in the dorsal horn (DH) and intermediolateral nucleus regions (IML). Materials and Methods: Anesthetized pigs underwent laminectomy to expose the spinal T2 section and a sternotomy to expose the heart for performing left anterior descending coronary artery ischemia (LAD) with and without intrathecal oxytocin (90ug) treatment. Electrocardiograms were recorded using a 56-channel mesh electrode to evaluate the activation recovery interval (ARI) and dispersion of repolarization (DOR) which are the markers for sympathoexcitation and arrhythmogenecity. Extracellular in-vivo spinal neural recordings were done by using a 64-channel microelectrode array inserted at the T2 segment of the spinal cord to record the activity of DH and IML neurons. Oxytocin was administered intrathecally at T1-T3. Spinal neural activity, ARI, and DOR were evaluated during myocardial ischemia with vs. without intrathecal oxytocin administration. Results: Sixteen Yorkshire pigs entered into this study. In 13 animals (LAD:7, LAD+OXT:6) ARI and DOR were evaluated during long LAD ischemia (1hr). ARI shortening due to LAD was mitigated by OXT (LAD:-33 ± 4 ms; LAD+OXT: -15 ± 1 ms, P=0.001). OXT decreased the LAD-induced augmented DOR (LAD: 2194± 310 ms2; LAD+OXT: 1099± 305 ms2, P=0.029). We have further evaluated the effect of OXT on short LAD ischemia (5 mins) and the impact of intrathecal OXT agonist on the spinal cord neural processing of myocardial ischemia in 3 pigs. Out of 88 recorded neurons, LAD increased the firing rate of more neurons than the LAD+OXT (LAD: increased 52, decreased 12 neurons; LAD+OXT: increased 16, decreased 14 neurons, P=0.007). The LAD-induced spinal cord hyperactivity was mitigated after intrathecal OXT administration (LAD:1.57 ± 0.52 Hz to LAD+OXT: 0.02 ± 0.22 Hz, P=0.0001). OXT also mitigated the reperfusion-induced spinal neuronal hyperactivity (LAD:2.16 ± 0.59 Hz to LAD+OXT: -0.36 ± 0.28 Hz, P<0.0001). OXT showed a similar effect in reducing the LAD-induced sympathoexcitation in these three animals (ARI shortening: LAD: -69 ± 14 ms; LAD+OXT: -38 ± 8 ms, P=0.035). Conclusion: Myocardial ischemia induces sympathoexcitation by increasing the spinal neural activity. OXT mitigates the adverse effect of myocardial ischemia by suppressing spinal neural hyperactivity. Funding: NIH (R01) HL136836 (Dr.Mahajan) and University of Pittsburgh Medical Center Competitive Medical Research Fund (Dr.Salavatian). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.