Chronic Stress Produces Persistent Increases in Plasma Corticosterone, Reductions in Brain and Cardiac Nitric Oxide Production, and Delayed Alterations in Endothelial Function in Young Prehypertensive Rats

This study was designed to investigate whether oxidative stress, nitric oxide (NO) deficiency and/or endothelial dysfunction (ED) are present in young borderline hypertensive rats (BHR) and whether these pathologies can be causally involved in the initiation of blood pressure (BP) increases. Additionally, we tested the hypothesis that crowding stress, experienced during the peripubertal period, may produce persistent or delayed disorders in corticosterone release, NO synthesis, oxidative status and/or endothelial function that could accelerate BP increases. To test these hypotheses, 5-week-old male BHR and normotensive Wistar-Kyoto rats (WKY) were either kept in control conditions (for 2 and 4 weeks, respectively) or exposed to social stress produced by crowding for 2 weeks (stress). After cessation of crowding, a group of rats of each phenotype was kept in control conditions for the next 2 weeks (post-stress). Systolic BP of 5-week-old BHR was significantly increased vs. age-matched WKY (127 ± 3 vs. 104 ± 3 mmHg, p < 0.01) and remained significantly higher throughout the course of the experiment. Despite elevated BP, no signs of oxidative damage to plasma lipids, NO deficiency or ED were observed in control BHR vs. age-matched WKY. Crowding stress elevated plasma corticosterone and accelerated BP increases only in BHR; these effects persisted 2 weeks post-stress. Crowding failed to induce oxidative damage to plasma lipids in either phenotype, but it produced persistent decreases in NO production in the hypothalamus and brainstem of both strains of rats, as well as in the hearts of BHR. In contrast, crowding failed to reduce NO production in the aortae or acetylcholine-induced relaxations of the femoral arteries in both strains investigated. However, significantly reduced aortic NO production was observed in BHR 2 weeks post-stress vs. age-matched controls, which was in agreement with reduced NO-dependent components of vasorelaxation. In conclusion, this study’s data showed that oxidative stress, NO deficiency and ED are not causally involved in initiation of blood pressure increase in BHR. However, exposure to stressful environments produced persistent increases in plasma corticosterone and reductions of brain and cardiac NO production followed by a delayed decrease in the NO-dependent component of endothelium-dependent relaxation—changes that collectively accelerated BP increases only in BHR

Chronic social stress increases nitric oxide-dependent vasorelaxation in normotensive rats

The aim of this study was to examine oxidative load and endothelium-dependent vasorelaxation in the serotonin pre-constricted femoral artery (FA) of Wistar-Kyoto (WKY) rats exposed to chronic social stress produced by crowding in the presence or absence of ascorbic acid (AsA) in working solution. Adult male rats were randomly divided into control (living space: 480 cm2/rat) or stressed (living space: 200 cm2/rat) groups for 8 weeks. Blood pressure and heart rate, determined using tail-cuff plethysmography, were not influenced by stress vs. control. Conjugated dienes (CD) and concentrations of thiobarbituric acid-reactive substances (TBARS) were measured in the left ventricle and liver (for assessment of oxidative load) and were found unchanged by chronic crowding. The nitric oxide (NO)-dependent component of endothelium-dependent relaxation was investigated in the FA using a wire myograph. In both the presence and absence of AsA, acetylcholine-induced relaxation of the FA of stressed rats significantly exceeded that of the controls, which was associated with an increase of the NO-dependent component. In conclusion, the data showed that chronic crowding did not produce oxidative stress in the organs investigated and indicate that elevation of NO production during chronic stress is an important way of adaptation, which may prevent normotensive rats from the development of stress-induced hypertension

Endothelial Dysfunction in Experimental Models of Arterial Hypertension: Cause or Consequence?

Hypertension is a risk factor for other cardiovascular diseases and endothelial dysfunction was found in humans as well as in various commonly employed animal experimental models of arterial hypertension. Data from the literature indicate that, in general, endothelial dysfunction would not be the cause of experimental hypertension and may rather be secondary, that is, resulting from high blood pressure (BP). The initial mechanism of endothelial dysfunction itself may be associated with a lack of endothelium-derived relaxing factors (mainly nitric oxide) and/or accentuation of various endothelium-derived constricting factors. The involvement and role of endothelium-derived factors in the development of endothelial dysfunction in individual experimental models of hypertension may vary, depending on the triggering stimulus, strain, age, and vascular bed investigated. This brief review was focused on the participation of endothelial dysfunction, individual endothelium-derived factors, and their mechanisms of action in the development of high BP in the most frequently used rodent experimental models of arterial hypertension, including nitric oxide deficient models, spontaneous (pre)hypertension, stress-induced hypertension, and selected pharmacological and diet-induced models

Hypertension and Cardiovascular Diseases: From Etiopathogenesis to Potential Therapeutic Targets

Cardiovascular diseases (CVDs) are the top cause of death worldwide, and arterial hypertension per se remains the major preventable cause of CVDs [...

The effect of omega- 3 polyunsaturated fatty acids on endothelial tight junction occludin expression in rat aorta during lipopolysaccharide-induced inflammation

Objective(s): Occludin is essential for proper assembly of tight junctions (TJs) which regulate paracellular endothelial permeability. Omega-3 polyunsaturated fatty acids (Ω-3 PUFA) protect endothelial barrier function against injury. Materials and Methods: We examined anti-inflammatory effect of Ω-3 PUFA intake (30 mg/kg/day for 10 days) on expression and location of occludin in the aorta of adult Wistar rats after a single dose of bacterial lipopolysaccharide (LPS, Escherichia coli, 1 mg/kg). The ultrastructure of TJs after LPS administration was also investigated. We measured plasma levels of C-reactive protein (CRP), Malondialdehyde (MDA) and CD68 expression and determined the total activity of NO synthase (NOS) in the aortic tissue. Results:LPS induced a significant decrease of occludin expression accompanied by structural alterations of TJs. Levels of CRP, MDA, CD68 and NOS activity were elevated after LPS injection compared to controls indicating presence of moderate inflammation. Ω-3 PUFA supplementation did not affect occludin expression in treated inflammatory group. However they reduced CRP and MDA concentration and CD68 expression, but conversely, they increased NOS activity compared to inflammatory group. Conclusion:Our results indicate that a single dose of LPS could have a long-term impact on occludin expression and thus contribute to endothelial barrier dysfunction. 10-day administration of Ω-3 PUFA had partial anti-inflammatory effects on health of rats without any effect on occludin expression

Preliminary Findings on the Effect of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles and Acute Stress on Selected Markers of Oxidative Stress in Normotensive and Hypertensive Rats

Several studies have reported that the administration of various nanoparticles in vivo can cause oxidative stress. The combination of ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) and acute stress was selected because, during intravenous application of a contrast agent, patients are exposed to psycho-emotional stress. This study was designed to investigate the effect of acute stress and USPIONs on selected markers of oxidative stress (antioxidant capacity, superoxide dismutase, glutathione peroxidase and catalase activities, levels of advanced oxidation protein products, protein carbonyls, lipoperoxides and 8-isoprostanes) in plasma and erythrocytes in normotensive Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the WKY and SHR groups, there was a significant main effect of genotype between groups on studied markers except protein carbonyls and lipoperoxides. In SHR, the combination of acute stress and USPIONs increased the antioxidant capacity of plasma and the selected enzyme activities of erythrocytes. In WKY, the combination of acute stress and USPIONs decreased the antioxidant capacity of erythrocytes and reduced levels of advanced oxidation protein products in plasma. Our study points to the fact that, when hypertensive subjects are treated with iron oxide nanoparticles, caution should be taken, especially in stress conditions, since they seem to be more vulnerable to oxidative stress produced by USPIONs

Preliminary Findings on the Effect of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles and Acute Stress on Selected Markers of Oxidative Stress in Normotensive and Hypertensive Rats

Several studies have reported that the administration of various nanoparticles in vivo can cause oxidative stress. The combination of ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) and acute stress was selected because, during intravenous application of a contrast agent, patients are exposed to psycho-emotional stress. This study was designed to investigate the effect of acute stress and USPIONs on selected markers of oxidative stress (antioxidant capacity, superoxide dismutase, glutathione peroxidase and catalase activities, levels of advanced oxidation protein products, protein carbonyls, lipoperoxides and 8-isoprostanes) in plasma and erythrocytes in normotensive Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the WKY and SHR groups, there was a significant main effect of genotype between groups on studied markers except protein carbonyls and lipoperoxides. In SHR, the combination of acute stress and USPIONs increased the antioxidant capacity of plasma and the selected enzyme activities of erythrocytes. In WKY, the combination of acute stress and USPIONs decreased the antioxidant capacity of erythrocytes and reduced levels of advanced oxidation protein products in plasma. Our study points to the fact that, when hypertensive subjects are treated with iron oxide nanoparticles, caution should be taken, especially in stress conditions, since they seem to be more vulnerable to oxidative stress produced by USPIONs

MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide

Reduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H2S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of Nos3 while plasma H2S levels correlated positively with gene expressions of H2S-producing enzymes Mpst, Cth and Cbs. MLN-4760 administration increased gene expression of Ace2, Sod1, Sod2, Gpx4 and Hmox1, which positively correlated with expression of Nfe2l2 gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H2S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H2S-producing enzymes that all correlated positively with elevated Nfe2l2 expression