Molecular hydrogen reduces mean and systolic blood pressure in various forms of hypertension, as well as inflammatory processes in lung tissue, in Wistar rats

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Abstract

Molecular hydrogen demonstrates antioxidant and anti-inflammatory properties. It has been shown to have a protective effect in several cardiovascular diseases. The aim of this work was to study the effect of breathing atmospheric air containing 4% hydrogen on the degree of development of monocrotaline-induced pulmonary hypertension and associated lung tissue inflammation, as well as the severity of renovascular hypertension in Wistar rats. Methods. Monocrotaline-induced pulmonary hypertension (MCT-PH) was used as a model of small circle hypertension. Three groups of animals were used in the experiment: "Control" – animals injected with monocrotaline solvent, "MCT-Control" and "MCT-H2" – groups injected with MCT once. The "Control" and "MCT-Control" groups breathed atmospheric air for 21 days, and the "MCT-H2" group breathed air containing 4% hydrogen. Inhalations were kept constant until 21 days. On day 21, haemodynamic parameters were measured under urethane anesthesia and lung samples were fixed for subsequent morphological analysis. Renovascular hypertension 1R1С (RVH) was used as a model of systemic hypertension. There were two groups in the experiment: RVH-C – rats breathed atmospheric air and RVH-H2 rats breathed air containing 4% hydrogen. During the experiment, systolic blood pressure (SBP) was measured and renal excretory function was assessed. On day 28, haemodynamic parameters were measured under urethane anesthesia. Results. In the MCT model, hydrogen had no effect on the haemodynamic symptoms of MCT hypertension, but decreased mean blood pressure (MBP), SBP and the measured markers of connective tissue remodeling in the lungs, TGF-β and MMP-9, and resulted in decreased tryptase secretion and mast cell counts. In the RVG model, hydrogen breathing decreased MBP, SBP and had no effect on renal excretory function. Conclusion. Inhalation of 4% hydrogen reduces systemic MBP and SBP in both models of arterial hypertension, reduces the severity of the inflammatory process, regulates the phenotypic and functional status of mast cells and inhibits the activity of profibrotic factors in lung tissue in MCT-PH. It is likely that the central action of hydrogen is combined with its anti-inflammatory and anti-fibrotic effects.

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About the authors

М. М. Artemieva

Lomonosov Moscow State University

Author for correspondence.
Email: marinka.artemieva@gmail.com
Russian Federation, Moscow

Т. А. Kuropatkina

Plekhanov Russian University of Economics; Peoples' Friendship University of Russia

Email: marinka.artemieva@gmail.com
Russian Federation, Moscow; Moscow

V. V. Shishkina

Voronezh State Medical University named after N.N. Burdenko

Email: marinka.artemieva@gmail.com
Russian Federation, Voronezh

D. V. Serebryanaya

Lomonosov Moscow State University; Pirogov Russian National Research Medical University

Email: marinka.artemieva@gmail.com
Russian Federation, Moscow; Moscow

D. А. Adasheva

Lomonosov Moscow State University

Email: marinka.artemieva@gmail.com
Russian Federation, Moscow

О. S. Medvedev

Lomonosov Moscow State University; National Medical Research Centre of Cardiology

Email: marinka.artemieva@gmail.com
Russian Federation, Moscow; Moscow

N. А. Medvedeva

Lomonosov Moscow State University

Email: marinka.artemieva@gmail.com
Russian Federation, Moscow

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2. Fig. 1. Schematic representation of the experimental setup.

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3. Fig. 2. Mean arterial pressure (a), systolic (b) and diastolic (c) arterial pressure on day 21 of the experiment. *MCT-H2 vs Control, MCT-Control, p < 0.05, One-way ANOVA. Numbers inside the columns indicate the number of animals.

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4. Fig. 3. Morphological features of the lung structures and mast cells of Wistar rats in the model of pulmonary hypertension. Staining methods: (a), (b), (e) - hematoxylin and eosin, (c), (d), (f) - Giemsa solution. (a) - control group, (b, c, d) - MKT-Control, (e, f) - MKT-H2. (a) - in the respiratory part of the lung, the elongated alveolar passages pass into thin-walled alveoli, signs of inflammatory infiltrate and stromal edema are observed; (b) - structural and functional changes in the arterial wall and obliteration of the lumen with media hypertrophy are revealed; (c) - mast cells (purple staining) infiltrate the stroma of the lung tissue, actively degranulate; (d) - neutrophils and plasma cells are noted in the locus; (e) – less pronounced edema of the interstitial structures and alveolar cells of the lung, an insignificant number of inflammatory infiltrate cells are located perivascularly; (f) – single mast cells in the field of vision without signs of degranulation. Magnification (a) – x 200, (b, c, e, f) – x 400, (d) – x 1000.

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5. Fig. 4. Histotopography and expression pattern of mast cell tryptase (a, b), TGF-β (c, d) and MMP-9 (e, f) in the lungs during the development of PH (b, d, f) and during PH with inhalation of 4% H2 (a, c, e). Specific brown staining for the immunohistochemical reaction reveals an accumulation of tryptase-positive mast cells with signs of degranulation in the interstitium of the lung tissue (b), while under the influence of inhalation of 4% H2 the expression of this protease decreases (a); infiltration of immunopositive cells with high TGF-β expression in the MKT-Control group (d) compared to a few TGF-β positive cells in the molecular hydrogen group (c); Low expression of MMP-9 (red, Cy3 label) against the background of co-collation with tryptase-positive mast cells (green, Alexa Fluor 488 label) in group (e) and accumulation of MMP-9 positive cells, mainly neutrophils (in accordance with the morphology of the cells) in the presence of tryptase-positive mast cells. Staining methods: (a, b, c, d) – immunohistochemical reaction, (e, f) – immunofluorescence staining. Magnification (a, b, d) – x 400; (c, e, f) – x 1000.

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6. Fig. 5. Hemodynamic parameters of awake (a) and anesthetized (b–d) Wistar rats with renovascular renal hypertension INH. (a) – SBP dynamics in awake rats, measured by indirect plethysmography. (b–d) hemodynamic parameters in anesthetized rats – (b) HR; (c) – mean BP; (d) – SBP; (e) – DBP. # – statistically significant differences between 1 and 3 points (p < 0.05) two-way ANOVA. * – statistically significant differences between groups (p < 0.05) by t-test for unrelated variables. ** – statistically significant differences between groups (p < 0.01) by t-test for unrelated variables. Numbers inside columns indicate the number of animals.

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7. Fig. 6. Evaluation of renal excretory function in Wistar rats with RVH. (a) – serum creatinine concentration; (b) – daily creatinine excretion; (c) – creatinine clearance; (d) – serum urea concentration; (e) – daily urea excretion. ** – statistically significant differences between pre- and postoperative values ​​(p < 0.01) by two-way ANOVA. *** – statistically significant differences between pre- and postoperative values ​​(p < 0.001) by two-way ANOVA. Numbers inside the columns indicate the number of animals.

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