Dual inhibition of NADPH oxidases and xanthine oxidase potently prevents salt-induced stroke in stroke-prone spontaneously hypertensive rats

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Oxidative stress has been implicated in the pathophysiology of cerebral stroke. As NADPH oxidases (NOXs) play major roles in the regulation of oxidative stress, we hypothesized that reduction of NOX activity by depletion of p22phox, an essential subunit of NOX complexes, would prevent cerebral stroke. To investigate this, we used the stroke-prone spontaneously hypertensive rat (SHRSP) and the p22phox-deleted congenic SHRSP. Although p22phox depletion reduced blood pressure under salt loading, it did not ameliorate oxidative stress or reduce the incidence of salt-induced stroke in SHRSPs. Additional pharmacological reduction of oxidative stress using antioxidant reagents with different mechanisms of action was necessary to prevent stroke, indicating that NOX was not the major target in salt-induced stroke in SHRSPs. On the other hand, oxidative stress measured based on urinary isoprostane levels showed significant correlations with blood pressure, stroke latency and urinary protein excretion under salt loading, suggesting an important role of oxidative stress per se in hypertension and hypertensive organ damage. Overall, our results imply that oxidative stress from multiple sources influences stroke susceptibility and other hypertensive disorders in salt-loaded SHRSPs.

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The authors thank Satoko Mishima, Masamichi Koike and Masaki Misumi for their skillful assistance in the histological evaluation.


This work was partly supported by JSPS KAKENHI 26293086 (to T.N.) and 17K08787 (to H.O.).

Author information

TN conceived, designed and supervised this study. DN, MZF, HMZ, and HO performed the experiments. TN, KF, DN, and HO analyzed the data and discussed the results. DN wrote the manuscript in consultation with TN and HO. All authors reviewed and approved the final version of the manuscript.

Correspondence to Hiroki Ohara.

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Ngarashi, D., Fujikawa, K., Ferdaus, M.Z. et al. Dual inhibition of NADPH oxidases and xanthine oxidase potently prevents salt-induced stroke in stroke-prone spontaneously hypertensive rats. Hypertens Res 42, 981–989 (2019). https://doi.org/10.1038/s41440-019-0246-2

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  • stroke
  • oxidative stress
  • p22phox
  • NADPH oxidase

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