scholarly journals Nebivolol combined with tetrahydrobiopterin affects diastolic function in spontaneously hypertensive rats via the nitric oxide/cyclic guanosine monophosphate signalling pathway

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoli Guan ◽  
Xiaoying Guan ◽  
Changhong Lu ◽  
Bo Shang ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Diastolic Dysfunction ◽  
Spontaneously Hypertensive Rats ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
No Production ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Myocardial Oxidative Stress

Abstract Background Hypertension is the the primary cause of diastolic heart failure. Oxidative stress plays an important role in cardiac diastolic dysfunction caused by hypertension. The occurrence of oxidative stress is related to the level of nitric oxide (NO) in the body. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. Nebivolol can reduce myocardial oxidative stress and increase NO activity. Therefore, we investigated the effects of monotherapy or combination therapy of different doses of BH4 and nebivolol on cardiac diastolic function in spontaneously hypertensive rats, and preliminarily expounded the related mechanisms. Methods Left ventricular function was evaluated by non-invasive echocardiographic assessment and invasive right carotid artery catheterization methods. ELISA was used to measure myocardial 3-nitrotyrosine content, NO production, and cyclic guanosine monophosphate (cGMP) concentration in the myocardium; quantitative real-time PCR (qRT-PCR) was used to determine endothelial nitric oxide synthase (eNOS), phospholamban and sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) mRNA expression levels; Western blot was used to detect the protein expression levels of eNOS and eNOS dimers in myocardial tissue, and immunohistochemical detection of cGMP expression in the myocardium was performed. Results Studies have shown that compared with those in the control group, NO generation and the expression level of myocardial eNOS mRNA, eNOS expression of dimers, phospholamban, SERCA2a and cGMP increased significantly after the combined intervention of BH4 and nebivolol, while the expression of 3-nitrotyrosine was significantly decreased. Conclusions The combined treatment group had a synergistic effect on reducing myocardial oxidative stress, increasing eNOS content, and increasing NO production, and had a more obvious protective effect on diastolic dysfunction through the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway.

Abstract 256: Renal Denervation Preconditions the Myocardium by Promoting Nitric Oxide Signaling and Attenuating Oxidative Stress in Spontaneously Hypertensive Rats

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
David J Polhemus ◽  
Juan Gao ◽  
Daniel R Kapusta ◽  
David J Lefer
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Spontaneously Hypertensive Rats ◽  
Renal Denervation ◽  
Ischemia Reperfusion ◽  
Treated Group ◽  
Hypertensive Rats ◽  
Carbonyl Content ◽  
Spontaneously Hypertensive ◽  
Myocardial Oxidative Stress

Background: Recent clinical studies suggest that renal denervation (RDN) not only decreases blood pressure (BP) and sympathetic nerve activity, but may also exert additional systemic cardioprotective actions. We investigated whether RDN preconditions the heart against subsequent myocardial ischemia/reperfusion (MI/R) injury in spontaneously hypertensive rats (SHR). Materials and Methods: SHR (20w old) received either bilateral radiofrequency (RF) RDN or sham RDN (Biosense Webster Stockert 70 RF generator). After 4w of BP recording, Plasma and left ventricle (LV) tissue were collected for measurement of nitric oxide (NO) metabolites, nitrite (NO2-, ion chromatography) and S-Nitrosothiol (RSNO). RT PCR was used to examine transcriptional changes. Colorimetric assays were used to quantify malondialdehyde (MDA) and carbonyl content. In additional studies, 4w after RDN (n = 8) or Sham (n = 9) treatment, SHR were subjected to 30m of left coronary artery ischemia followed by 24h reperfusion and myocardial infarct/area-at-risk (AAR) was determined. Results: 4w after treatment, mean BP was significantly decreased in RDN compared to Sham SHR (157±2 vs 142±2 mmHg, p < 0.05). Plasma NO2- levels were elevated 4w following RDN (p < 0.01). Cardiac NO2- levels increased from 2.6 to 3.2 nmol/mg (p < 0.05) and RSNO levels increased from 0.5 to 1.1 nmol/mg (p < 0.05) following RDN. Moreover, myocardial oxidative stress was markedly attenuated as measured by carbonyl content (p < 0.05) and MDA levels (p < 0.01). Greater transcription of antioxidants, SOD1 (p < 0.05) and GPX-1 (p < 0.05) were also observed in the RDN treated group. SHR receiving RDN therapy exhibited a trend in infarct size reduction (42% per AAR reduction, p = 0.09) compared to sham following MI/R. We observed 2-fold greater survival in the RDN treated group (88%, 7 of 8) compared to sham (44%, 4 of 9) following MI/R. Conclusions: RDN produced a sustained elevation in NO bioavailability and signaling in the heart and blood. Additionally, RDN attenuated myocardial oxidative stress and augmented the antioxidant defense system in SHR. Although further studies are warranted, preliminary results indicate that these mechanisms may promote myocardial preconditioning and improve survival in the setting of MI/R injury.

scholarly journals Increased Blood Pressure Causes Lymphatic Endothelial Dysfunction via Oxidative Stress in Spontaneously Hypertensive Rats

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 598-606
Author(s):  
Masashi Mukohda ◽  
Risuke Mizuno ◽  
Hiroshi Ozaki
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Sodium Nitroprusside ◽  
P38 Mapk ◽  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

The lymphatic system is involved in the pathogenesis of edema, inflammation, and cancer metastasis. Because lymph vessels control fluid electrolytes and volume balance, changes in lymphatic activity can be expected to alter systemic blood pressure. This study examined possible changes in lymphatic contractile properties in spontaneously hypertensive rats (SHR). Thoracic ducts isolated from 10- to 12-week-old SHR exhibited either decreased acetylcholine-induced endothelium-dependent relaxation or sodium nitroprusside-induced endothelium-independent relaxation compared with age-matched Wister-Kyoto rats. The impairment in acetylcholine responsiveness was more pronounced than sodium nitroprusside responsiveness. N-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor blunted acetylcholine-induced relaxation in Wister-Kyoto rats, indicating an involvement of endothelial nitric oxide production. Endothelial dysfunction in lymph vessels of SHR was attenuated by tempol (a superoxide dismutase mimetic), apocynin, or VAS-2870 (NADPH oxidase inhibitors). Consistent with these observations, nitrotyrosine levels were significantly elevated in SHR, indicative of increased oxidative stress. In addition, protein expression of NADPH oxidase 2 and phosphorylation of p47 phox (Ser345) were significantly increased in SHR. Further, SB203580 (a p38 MAPK inhibitor) restored the acetylcholine-induced relaxation in SHR. It is notable that 4-week-old SHR, which exhibited normal blood pressure, did not show any decreased activity of acetylcholine- or sodium nitroprusside-induced relaxation. Additionally, antihypertensive treatment of 4-week-old SHR with hydrochlorothiazide and reserpine or hydrochlorothiazide and hydralazine for 6 weeks completely restored lymphatic endothelial dysfunction. We conclude that contractile activity of lymphatic vessels is functionally impaired with the development of increasing blood pressure, which is mediated through increased oxidative stress via the p38 MAPK/NADPH oxidase 2 pathway.

Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats

2004 ◽  
Vol 96 (6) ◽  
pp. 2088-2096 ◽  
Author(s):  
Drew A. Graham ◽  
James W. E. Rush
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Exercise Training ◽  
Spontaneously Hypertensive Rats ◽  
No Synthase ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Endothelial No Synthase ◽  
Endothelium Dependent Relaxation

The present study examined in vitro vasomotor function and expression of enzymes controlling nitric oxide (NO) bioavailability in thoracic aorta of adult male normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that either remained sedentary (Sed) or performed 6 wk of moderate aerobic exercise training (Ex). Training efficacy was confirmed by elevated maximal activities of both citrate synthase ( P = 0.0024) and β-hydroxyacyl-CoA dehydrogenase ( P = 0.0073) in the white gastrocnemius skeletal muscle of Ex vs. Sed rats. Systolic blood pressure was elevated in SHR vs. WKY ( P < 0.0001) but was not affected by Ex. Despite enhanced endothelium-dependent relaxation to 10-8 M ACh in SHR vs. WKY ( P = 0.0061), maximal endothelium-dependent relaxation to 10-4 M ACh was blunted in Sed SHR (48 ± 12%) vs. Sed WKY (84 ± 6%, P = 0.0067). Maximal endothelium-dependent relaxation to 10-4 M ACh was completely restored in Ex SHR (93 ± 9%) vs. Sed SHR ( P = 0.0011). Nω-nitro-l-arginine abolished endothelium-dependent relaxation in all groups ( P ≤ 0.0001) and caused equal vasocontraction to maximal ACh in Sed SHR and Ex SHR. Endothelium-independent relaxation to sodium nitroprusside was similar in all groups. Protein levels of endothelial NO synthase were higher in SHR vs. WKY ( P = 0.0157) and in Ex vs. Sed ( P = 0.0536). Protein levels of the prooxidant NAD(P)H oxidase subunit, gp91phox, were higher in SHR vs. WKY ( P < 0.0001) and were diminished in Ex vs. Sed ( P = 0.0557). Levels of the antioxidant SOD-1, -2, and catalase enzymes were lower in SHR vs. WKY (all P ≤ 0.0005) but were not altered by Ex. Thus elevated gp91phox-dependent oxidative stress and reduced antioxidant capacity likely contributed to impaired endothelium-dependent vasorelaxation in Sed SHR. Furthermore, reduced gp91phox-dependent oxidative stress and enhanced endothelial NO synthase-derived NO likely contributed to restored endothelium-dependent vasorelaxation in Ex SHR.

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