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Updated: Apr 16, 2026

Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds
Published on: February 16, 2022
[On the mechanism of radioprotective effect of NO-synthase inhibitors]
Abstract:
We studied the influence on hemodynamics and radioprotective activity of two inhibitors of NO-synthase (NOS)--isothiourea derivatives with different NOS isoform selectivity: T1023--a selective inhibitor of endothelial and inducible NOS; and NTT2--a highly selective inhibitor of neuronal NOS. Both compounds at a dose of 1/7 LD50/15 caused a vasopressive effect and baroreflex response in normal Wistar rats. However, the nature of hemodynamic changes was qualitatively different. T1023 caused a prolonged elevation of vascular tone and reflex shift resulted in a significant and lasting reduction in the systemic blood flow (35-45%), which created conditions for the development of circulatory hypoxia. The use of NTT2 caused a reflex change in hemodynamics accompanied by vasodilation; and systemic blood flow was maintained at the initial level. T1023 effectively protected mice subjected to 10 Gy γ-irradiation and their bone marrow stem cells irradiated with 6 Gy, not yielding to the radioprotective effect of cystamine. NTT2 at these doses did not show any radioprotective effect. The obtained results support the leading mechanism of the radioprotective effect of NOS inhibitors is the induction of hypoxia. With this mechanism of action a significant radioprotective activity can be expected for the inhibitors which effectively suppress primarily endothelial NOS.
Insights
Selective inhibition of endothelial nitric oxide synthase (NOS) induces hypoxia, conferring radioprotective effects. This suggests potential for developing new radioprotectors targeting endothelial NOS.
Area of Science:
- Pharmacology
- Radioprotection
- Physiology
Context:
- Nitric oxide synthase (NOS) inhibitors are explored for radioprotective potential.
- Understanding NOS isoform selectivity is crucial for predicting therapeutic effects.
- Hemodynamic responses to NOS inhibition vary based on isoform selectivity.
Purpose:
- To investigate the hemodynamic and radioprotective effects of two isothiourea derivatives with differing NOS isoform selectivity.
- To determine the role of NOS isoform selectivity in mediating radioprotection.
- To elucidate the mechanism underlying the radioprotective activity of NOS inhibitors.
Summary:
- T1023, an endothelial and inducible NOS inhibitor, induced prolonged hypotension and significant reduction in systemic blood flow, creating hypoxic conditions.
- NTT2, a neuronal NOS inhibitor, caused vasodilation and maintained systemic blood flow.
- T1023 demonstrated significant radioprotective effects in mice and bone marrow stem cells, while NTT2 did not.
- Radioprotection by NOS inhibitors appears to be mediated by hypoxia induction, particularly via endothelial NOS suppression.
Impact:
- The findings support hypoxia induction as the primary mechanism for radioprotection by NOS inhibitors.
- Selective inhibition of endothelial NOS is identified as a key factor for effective radioprotective activity.
- This research provides a basis for designing novel radioprotectors targeting endothelial NOS for radiation therapy and exposure mitigation.
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