Free radical biology & medicine · 2025
Beneficial effects of mitochondria-targeted S-nitrosothiol on outcomes after cardiac arrest and resuscitation in rats.
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Endo Yusuke, Takegawa Ryosuke, Murphy Michael P, Becker Lance B, Hayashida Kei
Аннотация
BACKGROUND: Mitochondria-targeted S-nitrosothiol (MitoSNO) is thought to protect against ischemia-reperfusion injury by suppressing reactive oxygen species production upon reperfusion. We investigated whether intravenous MitoSNO administration after resuscitation improves outcomes following cardiac arrest (CA) in rats.
METHODS: Adult male rats were subjected to 10 min of asphyxial CA followed by cardiopulmonary resuscitation (CPR). Upon return of spontaneous circulation (ROSC), animals were randomized to receive either vehicle or MitoSNO (400 ng/kg total), administered intravenously in two doses: immediately and 1 h post-CA. The dosing regimen was selected based on findings from an exploratory dose-titration study. Neurological function and survival were assessed over a 72-h period. Cardiac function was evaluated using transthoracic echocardiography, while cerebral blood flow (CBF) was measured via laser speckle contrast imaging. Brain injury and oxidative stress were assessed through Fluoro-Jade B staining, western blotting, and enzyme-linked immunosorbent assay.
RESULTS: MitoSNO significantly improved 72-h survival and neurological function compared to vehicle controls (100 % vs. 40 %, P < 0.05). Echocardiography showed enhanced left ventricular ejection fraction and cardiac index at 24 h post-ROSC in MitoSNO-treated animals compared with vehicle (89.8 ± 3.1 % vs 83.8 ± 7.5 %; P < 0.05, 69.2 ± 13.2 ml/min/100g vs 46.3 ± 11.6 ml/min/100g; P < 0.01). MitoSNO also attenuated post-CA cerebral hypoperfusion, as evidenced by preserved relative CBF on laser speckle imaging. Western blotting revealed reduced levels of 3-nitrotyrosine and cleaved caspase-3 in brain tissue, indicating decreased nitrosative stress and apoptosis. Immunohistochemistry demonstrated suppression of neuronal degeneration in vulnerable brain regions.
CONCLUSIONS: Post-resuscitation administration of MitoSNO significantly improved survival and neurological outcomes following CA in rats. These benefits were associated with enhanced cardiac function, preserved cerebral perfusion, and reduced oxidative stress and apoptosis in the brain.
METHODS: Adult male rats were subjected to 10 min of asphyxial CA followed by cardiopulmonary resuscitation (CPR). Upon return of spontaneous circulation (ROSC), animals were randomized to receive either vehicle or MitoSNO (400 ng/kg total), administered intravenously in two doses: immediately and 1 h post-CA. The dosing regimen was selected based on findings from an exploratory dose-titration study. Neurological function and survival were assessed over a 72-h period. Cardiac function was evaluated using transthoracic echocardiography, while cerebral blood flow (CBF) was measured via laser speckle contrast imaging. Brain injury and oxidative stress were assessed through Fluoro-Jade B staining, western blotting, and enzyme-linked immunosorbent assay.
RESULTS: MitoSNO significantly improved 72-h survival and neurological function compared to vehicle controls (100 % vs. 40 %, P < 0.05). Echocardiography showed enhanced left ventricular ejection fraction and cardiac index at 24 h post-ROSC in MitoSNO-treated animals compared with vehicle (89.8 ± 3.1 % vs 83.8 ± 7.5 %; P < 0.05, 69.2 ± 13.2 ml/min/100g vs 46.3 ± 11.6 ml/min/100g; P < 0.01). MitoSNO also attenuated post-CA cerebral hypoperfusion, as evidenced by preserved relative CBF on laser speckle imaging. Western blotting revealed reduced levels of 3-nitrotyrosine and cleaved caspase-3 in brain tissue, indicating decreased nitrosative stress and apoptosis. Immunohistochemistry demonstrated suppression of neuronal degeneration in vulnerable brain regions.
CONCLUSIONS: Post-resuscitation administration of MitoSNO significantly improved survival and neurological outcomes following CA in rats. These benefits were associated with enhanced cardiac function, preserved cerebral perfusion, and reduced oxidative stress and apoptosis in the brain.