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Nitric oxide and the brain. Part 1: Mechanisms of regulation, transport and effects on the developing brain


Apart from its known actions as a pulmonary vasodilator, nitric oxide (NO) is a key signal mediator in the neonatal brain. Despite the extensive use of NO for pulmonary artery hypertension (PAH), its actions in the setting of brain hypoxia and ischemia, which co-exists with PAH in 20–30% of affected infants, are not well established. This review focuses on the mechanisms of actions of NO covering the basic, translational, and clinical evidence of its neuroprotective and neurotoxic properties. In this first part, we present the physiology of transport and delivery of NO to the brain and the regulation of cerebrovascular and systemic circulation by NO, as well the role of NO in the development of the immature brain.


  • NO can be transferred from the site of production to the site of action rapidly and affects the central nervous system.

  • Inhaled NO (iNO), a commonly used medication, can have significant effects on the neonatal brain.

  • NO regulates the cerebrovascular and systemic circulation and plays a role in the development of the immature brain.

  • This review describes the properties of NO under physiologic conditions and under stress.

  • The impact of this review is that it describes the effects of NO, especially regarding the vulnerable neonatal brain, and helps understand the conditions that could contribute to neurotoxicity or neuroprotection.

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Fig. 1: Cellular interactions of NO.


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R.S. holds the William Buchanan Chair in Pediatrics, and L.C. is supported by NIH Grant 1R01NS102617-01.

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D.A. contributed to the concept of the paper, wrote the initial and revised drafts of this manuscript, and approved the final manuscript as submitted; R.S. contributed to the conceptualization of the paper, reviewed and revised the manuscript, and approved the final manuscript as submitted; L.C. contributed to the conceptualization of the paper, reviewed and revised the manuscript, and approved the final manuscript as submitted.

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Correspondence to Dimitrios Angelis.

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R.S. is on the Scientific Advisory Council of Mallinckrodt Pharmaceuticals and had no role in the development of this review. D.A. and L.C. have no conflicts of interest to disclose.

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Angelis, D., Savani, R. & Chalak, L. Nitric oxide and the brain. Part 1: Mechanisms of regulation, transport and effects on the developing brain. Pediatr Res 89, 738–745 (2021).

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