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. 2023 Apr;55(4):529-539.
doi: 10.1007/s00726-023-03246-9. Epub 2023 Feb 19.

Urinary excretion of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine is positively related to nitric oxide level in tissues of normotensive and hypertensive rats

Dominika Szlęzak  1 , Marcin Ufnal  2 , Adrian Drapała  2 , Emilia Samborowska  3 , Maria Wróbel  4
Affiliations

Urinary excretion of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine is positively related to nitric oxide level in tissues of normotensive and hypertensive rats

Dominika Szlęzak et al. Amino Acids. 2023 Apr.

Abstract

Nitric oxide (NO) is one of the gaseous transmitters which play a very important role in the regulation of the circulatory system. Decreased NO availability is associated with hypertension, cardiovascular and kidney diseases. Endogenous NO is generated enzymatically by nitric oxide synthase (NOS) depending on the availability of the substrate, cofactors, or presence/absence of inhibitors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). The objective of this study was to evaluate the potential relationship between NO level in rat tissues (heart and kidneys) and the concentrations of endogenous metabolites related to NO in plasma and urine. The experiment was carried out with 16- and 60-week-old male Wistar Kyoto (WKY) and age-matched male Spontaneously Hypertensive Rats (SHR). NO level in tissue homogenates was determined by the colorimetric method. RT-qPCR was used to verify the expression of the eNOS (endothelial NOS) gene. Plasma and urine concentrations of arginine, ornithine, citrulline, and dimethylarginines were examined by the UPLC-MS/MS method. 16-week-old WKY rats had the highest tissue NO and plasma citrulline levels. Furthermore, 16-week-old WKY rats showed higher urinary excretion of ADMA/SDMA compared to other experimental groups, however, plasma concentrations of arginine, ADMA, and SDMA were comparable between the groups. In conclusion, our research shows that hypertension and aging decrease tissue NO levels and are associated with reduced urinary excretion of NOS inhibitors, i.e., ADMA and SDMA.

Keywords: Aging; Asymmetric dimethylarginine (ADMA); Hypertension; Nitric oxide; Symmetric dimethylarginine (SDMA).

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Conflict of interest statement

The authors declare no competing interests.

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Biochemical pathways related to nitric oxide biosynthesis. ADMA asymmetric dimethylarginine, ASL argininosuccinate lyase, ASS argininosuccinate synthase, ATS arginyl-tRNA synthetase, DDAH dimethylarginine dimethylaminohydrolase, DMA dimethylamine, NO nitric oxide, NOS nitric oxide synthase, OAT ornithine aminotransferase, OTC ornithine transcarbamylase, PRMTs protein arginine N-methyltransferases, SDMA symmetric dimethylarginine
Fig. 2
Fig. 2
Total nitrate/nitrite concentrations in the hearts (A) and kidneys (B) of rats. Values represent an arithmetic mean ± SD of 6–12 repetitions for 2–4 animals per group. 16-WKY 16-week-old WKY rats, 60-WKY 60-week-old WKY rats, 16-SHR 16-week-old SHRs, 60-SHR 60-week-old SHRs. *p < 0.05 SHR vs. WKY of the same age, #p < 0.05 60-week-old vs. 16-week-old
Fig. 3
Fig. 3
Expression of the eNOS gene in the hearts (A) and kidneys (B) of rats. Values represent an arithmetic mean ± SD (n = 3 animals per group). Each value is the mean of at least two independent experiments. 16-WKY 16-week-old WKY rats, 60-WKY 60-week-old WKY rats, 16-SHR 16-week-old SHRs, 60-SHR 60-week-old SHRs. *p < 0.05 SHR vs. WKY of the same age, #p < 0.05 60-week-old vs. 16-week-old
Fig. 4
Fig. 4
Plasma concentrations (A) and urinary excretion (B) of NO-related pathway endogenous metabolites in rats. The concentrations in the urine samples were normalized to 24-h urinary excretion. Values represent an arithmetic mean ± SD (n = 6–9 animals per group). The colored circles show the individual data values. 16-WKY 16-week-old WKY rats, 60-WKY 60-week-old WKY rats, 16-SHR 16-week-old SHRs, 60-SHR 60-week-old SHRs, ARG arginine, CIT citrulline, ORN ornithine, < LOQ below the limit of quantification. The quantification limits were 4.03 µM for arginine, 5.04 µM for ornithine, and 5.85 µM for citrulline. *p < 0.05 SHR vs. WKY of the same age, #p < 0.05 60-week-old vs. 16-week-old
Fig. 5
Fig. 5
Plasma concentrations (A) and urinary excretion (B) of ADMA and SDMA in rats. The concentrations in the urine samples were normalized to 24-h urinary excretion. Values represent an arithmetic mean ± SD (n = 6–9 animals per group). The colored circles show the individual data values. 16-WKY 16-week-old WKY rats, 60-WKY 60-week-old WKY rats, 16-SHR 16-week-old SHRs, 60-SHR 60-week-old SHRs, ADMA asymmetric dimethylarginine, SDMA symmetric dimethylarginine. The quantification limits were 0.03 µM for ADMA and 0.02 µM for SDMA. *p < 0.05 SHR vs. WKY of the same age, #p < 0.05 60-week-old vs. 16-week-old
Fig. 6
Fig. 6
Proposed dependence between urinary excretion of dimethylarginines and NO level in tissues of normotensive/hypertensive rats of different ages. ADMA asymmetric dimethylarginine, NO nitric oxide, SDMA symmetric dimethylarginine
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