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Activation of arginase II by asymmetric dimethylarginine and homocysteine in hypertensive rats induced by hypoxia: a new model of nitric oxide synthesis regulation in hypertensive processes?

Hypertension Research volume 44, pages 263–275 (2021)Cite this article

Abstract

In recent years, the increase in blood pressure at high altitudes has become an interesting topic among high-altitude researchers. In our animal studies using Wistar rats, we observed the existence of two rat populations that exhibit differential physiological responses during hypoxic exposure. These rats were classified as hypoxia-induced hypertensive rats and nonhypertensive rats. A decrease in nitric oxide levels was reported in different hypertension models associated with increased concentrations of asymmetric dimethylarginine (ADMA) and homocysteine, and we recently described an increase in arginase type II expression under hypoxia. ADMA and homocysteine decrease nitric oxide (NO) bioavailability; however, whether ADMA and homocysteine have a regulatory effect on arginase activity and therefore regulate another NO synthesis pathway is unknown. Therefore, the aim of this study was to measure basal ADMA and homocysteine levels in hypoxia-induced hypertensive rats and evaluate their effect on arginase II activity. Our results indicate that hypoxia-induced hypertensive rats presented lower nitric oxide concentrations than nonhypertensive rats, associated with higher concentrations of homocysteine and ADMA. Hypoxia-induced hypertensive rats also presented lower dimethylarginine dimethylaminohydrolase-2 and cystathionine β-synthase levels, which could explain the high ADMA and homocysteine levels. In addition, we observed that both homocysteine and ADMA had a significant effect on arginase II activation in the hypertensive rats. Therefore, we suggest that ADMA and homocysteine have dual regulatory effects on NO synthesis. The former has an inhibitory effect on eNOS, and the latter has a secondary activating effect on arginase II. We propose that arginase II is activated by AMDA and homocysteine in hypoxia-induced hypertensive rats.

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Acknowledgements

We acknowledge CONICYT for a scientific research grant from FONDECYT (11075096).

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  1. Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile

    Vasthi López & Fernando A. Moraga

  2. Departamento de Bioquímica, Facultad de Ciencias Biológicas, Universidad de Concepción. Barrio Universitario s/n, Concepción, Chile

    Elena Uribe

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López, V., Uribe, E. & Moraga, F.A. Activation of arginase II by asymmetric dimethylarginine and homocysteine in hypertensive rats induced by hypoxia: a new model of nitric oxide synthesis regulation in hypertensive processes?. Hypertens Res 44, 263–275 (2021). https://doi.org/10.1038/s41440-020-00574-1

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