Soluble Guanylate Cyclase-Mediated Relaxation in Aortas from Rats with Renovascular Hypertension

Pharmacology ◽  
2021 ◽  
pp. 1-6
Author(s):  
Masashi Tawa ◽  
Takashi Shimosato ◽  
Keisuke Nakagawa ◽  
Tomio Okamura ◽  
Mamoru Ohkita
Keyword(s):  
Renovascular Hypertension ◽  
Guanylate Cyclase ◽  
Sham Group ◽  
Soluble Guanylate Cyclase ◽  
Thiobarbituric Acid ◽  
Left Renal Artery ◽  
Thiobarbituric Acid Reactive Substances ◽  
No Bioavailability ◽  
The Impact ◽  
Regulation Of Vascular Tone

Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas. Renovascular hypertension was induced by partially clipping the left renal artery (2-kidneys, 1-clip; 2K1C) for 10 weeks. Systolic, diastolic, and mean arterial pressures were significantly increased in the 2K1C group when compared with the sham group. In addition, plasma thiobarbituric acid reactive substances and aortic superoxide generation were significantly enhanced in the 2K1C group when compared with those in the sham group. The vasorelaxant response of isolated aortas to the sGC stimulator BAY 41-2272 (NO-sensitive sGC agonist) was comparable between the sham and 2K1C groups. Likewise, the sGC activator BAY 60-2770 (NO-insensitive sGC agonist)-induced relaxation did not differ between the sham and 2K1C groups. In addition, the cGMP mimetic 8-Br-cGMP (protein kinase G agonist) induced similar relaxation in both groups. Furthermore, there were no differences in BAY 41-2272-stimulated and BAY 60-2770-stimulated cGMP generation between the groups. These findings suggest that the balance between NO-sensitive and NO-insensitive forms of sGC is maintained during renovascular hypertension. Therefore, sGC might not be responsible for the reduced NO bioavailability observed during renovascular hypertension.

scholarly journals Buprenorphine and Methadone as Opioid Maintenance Treatments for Heroin-Addicted Patients Induce Oxidative Stress in Blood

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Christonikos Leventelis ◽  
Nikolaos Goutzourelas ◽  
Aikaterini Kortsinidou ◽  
Ypatios Spanidis ◽  
Georgia Toulia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Thiobarbituric Acid ◽  
Redox Status ◽  
Protein Carbonyls ◽  
Healthy Individuals ◽  
Thiobarbituric Acid Reactive Substances ◽  
Antioxidant Defence ◽  
Total Antioxidant ◽  
Beneficial Action ◽  
The Impact

Buprenorphine and methadone are two substances widely used in the substitution treatment of patients who are addicted to opioids. Although it is known that they partly act efficiently towards this direction, there is no evidence regarding their effects on the redox status of patients, a mechanism that could potentially improve their action. Therefore, the aim of the present investigation was to examine the impact of buprenorphine and methadone, which are administered as substitutes to heroin-dependent patients on specific redox biomarkers in the blood. From the results obtained, both the buprenorphine (n=21) and the methadone (n=21) groups exhibited oxidative stress and compromised antioxidant defence. This was evident by the decreased glutathione (GSH) concentration and catalase activity in erythrocytes and the increased concentrations of thiobarbituric acid reactive substances (TBARS) and protein carbonyls in the plasma, while there was no significant alteration of plasma total antioxidant capacity (TAC) compared to the healthy individuals (n=29). Furthermore, methadone revealed more severe oxidant action compared to buprenorphine. Based on relevant studies, the tested substitutes mitigate the detrimental effects of heroin on patient redox status; still it appears that they need to be boosted. Therefore, concomitant antioxidant administration could potentially enhance their beneficial action, and most probably, buprenorphine that did not induce oxidative stress in such a severe mode as methadone, on the regulation of blood redox status.

scholarly journals cGMP modulation therapeutics for sickle cell disease

2019 ◽  
Vol 244 (2) ◽  
pp. 132-146 ◽  
Author(s):  
Nicola Conran ◽  
Lidiane Torres
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cell Transplant ◽  
Cell Disease ◽  
Chronic Complications ◽  
Intracellular Cgmp ◽  
No Bioavailability ◽  
Sgc Stimulators

Sickle cell disease (SCD) is an inherited disease caused by the production of abnormal hemoglobin (Hb) S, whose deoxygenation-induced polymerization results in red blood cell (RBC) sickling and numerous pathophysiological consequences. SCD affects approximately 300,000 newborns worldwide each year and is associated with acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. Chronic intravascular hemolysis in SCD significantly reduces vascular nitric oxide (NO) bioavailability, consequently decreasing intracellular signaling via cyclic guanosine monophosphate (cGMP), in turn diminishing vasodilation and contributing to the inflammatory mechanisms that trigger vaso-occlusive processes. Oxidative stress may further reduce NO bioavailability in SCD and can oxidize the intracellular enzyme target of NO, soluble guanylate cyclase (sGC), rendering it inactive. Increasing intracellular cGMP-dependent signaling constitutes an important pharmacological therapeutic approach for SCD with a view to augmenting vasodilation, and reducing inflammatory mechanisms, as well as for increasing the production of anti-polymerizing fetal Hb in erythroid cells. Pharmacological agents under pre-clinical and clinical investigation for SCD include NO-based therapeutics to augment NO bioavailability, as well as heme-dependent sGC stimulators and heme-independent sGC activators that directly stimulate native and oxidized sGC, respectively, therefore bypassing the need for vascular NO delivery. Additionally, the phosphodiesterases (PDEs) that degrade intracellular cyclic nucleotides with specific cellular distributions are attractive drug targets for SCD; PDE9 is highly expressed in hematopoietic cells, making the use of PDE9 inhibitors, originally developed for use in neurological diseases, a potential approach that could rapidly amplify intracellular cGMP concentrations in a relatively tissue-specific manner. Impact statement Sickle cell disease (SCD) is one of the most common inherited diseases and is associated with a reduced life expectancy and acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. At present, treatment of SCD is limited to hematopoietic stem cell transplant, transfusion, and limited options for pharmacotherapy, based principally on hydroxyurea therapy. This review highlights the importance of intracellular cGMP-dependent signaling pathways in SCD pathophysiology; modulation of these pathways with soluble guanylate cyclase (sGC) stimulators or phosphodiesterase (PDE) inhibitors could potentially provide vasorelaxation and anti-inflammatory effects, as well as elevate levels of anti-sickling fetal hemoglobin.

scholarly journals High-fat diet-induced obesity leads to increased NO sensitivity of rat coronary arterioles: role of soluble guanylate cyclase activation

2008 ◽  
Vol 294 (6) ◽  
pp. H2558-H2564 ◽  
Author(s):  
Eva Jebelovszki ◽  
Csaba Kiraly ◽  
Nora Erdei ◽  
Attila Feher ◽  
Eniko T. Pasztor ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Saturated Fat ◽  
Normal Diet ◽  
Coronary Perfusion ◽  
Similar Reduction ◽  
Obese Rats ◽  
The Impact ◽  
Deta Nonoate ◽  
Coronary Arterioles

The impact of obesity on nitric oxide (NO)-mediated coronary microvascular responses is poorly understood. Thus NO-mediated vasomotor responses were investigated in pressurized coronary arterioles (∼100 μm) isolated from lean (on normal diet) and obese (fed with 60% of saturated fat) rats. We found that dilations to acetylcholine (ACh) were not significantly different in obese and lean rats (lean, 83 ± 4%; and obese, 85 ± 3% at 1 μM), yet the inhibition of NO synthesis with Nω-nitro-l-arginine methyl ester reduced ACh-induced dilations only in vessels of lean controls. The presence of the soluble guanylate cyclase (sGC) inhibitor oxadiazolo-quinoxaline (ODQ) elicited a similar reduction in ACh-induced dilations in the two groups of vessels (lean, 60 ± 11%; and obese, 57 ± 3%). Dilations to NO donors, sodium nitroprusside (SNP), and diethylenetriamine (DETA)-NONOate were enhanced in coronary arterioles of obese compared with lean control rats (lean, 63 ± 6% and 51 ± 5%; and obese, 78 ± 5% and 70 ± 5%, respectively, at 1 μM), whereas dilations to 8-bromo-cGMP were not different in the two groups. In the presence of ODQ, both SNP and DETA-NONOate-induced dilations were reduced to a similar level in lean and obese rats. Moreover, SNP-stimulated cGMP immunoreactivity in coronary arterioles and also cGMP levels in carotid arteries were enhanced in obese rats, whereas the protein expression of endothelial NOS and the sGC β1-subunit were not different in the two groups. Collectively, these findings suggest that in coronary arterioles of obese rats, the increased activity of sGC leads to an enhanced sensitivity to NO, which may contribute to the maintenance of NO-mediated dilations and coronary perfusion in obesity.

Chronic hypoxia alters glucose utilization during GSH-dependent detoxication in rat small intestine

1998 ◽  
Vol 274 (2) ◽  
pp. G376-G384 ◽  
Author(s):  
Terry S. Legrand ◽  
Tak Yee Aw
Keyword(s):  
Glucose Utilization ◽  
Lipid Peroxide ◽  
Thiobarbituric Acid ◽  
Sprague Dawley ◽  
Thiobarbituric Acid Reactive Substances ◽  
Disulfide Reduction ◽  
Sprague Dawley Rats ◽  
The Impact

We showed that hypoxia alters glutathione (GSH)-dependent detoxication and induces mucosal metabolic instability. To determine the impact of these changes and the role of reductant supply in intestinal lipid peroxide disposition, pair-fed (16 g/day) Sprague-Dawley rats were exposed to air (20.9% O2; n = 6) or 10% O2( n = 6) for 10 days. Jejunal and ileal everted sacs were exposed to 75 μM peroxidized fish oil with or without 10 mM glucose or 1 mM GSH. Peroxide transport was determined as the abluminal recovery of thiobarbituric acid-reactive substances. Peroxide recovery in hypoxic intestine was twice that in normoxic intestine. Addition of GSH and glucose did not affect peroxide recovery, indicating reduced intracellular GSH-dependent metabolism and enhanced output by the hypoxic intestine. Glucose uptake by normoxic and hypoxic intestine is similar, whereas its utilization for detoxication is decreased in hypoxic cells. Determination of NADPH supply indicates that decreased glucose availability for NADPH production during hypoxia impairs GSH disulfide reduction, compromises hydroperoxide metabolism, and increases peroxide output from hypoxic intestine.

Effect of craniotomy on oxidative stress and its effect on plasma l-carnitine levels

2014 ◽  
Vol 92 (11) ◽  
pp. 913-916 ◽  
Author(s):  
Huan-ting Li ◽  
Zhen-huan Zhao ◽  
Hai-yan Ding ◽  
Le-xin Wang ◽  
Yu Cao
Keyword(s):  
Oxidative Stress ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Thiobarbituric Acid ◽  
Thiobarbituric Acid Reactive Substances ◽  
Before And After ◽  
Baseline Values ◽  
The Mean ◽  
Total Antioxidative Capacity ◽  
The Impact

Objective: to investigate the impact of craniotomy on oxidative stress and its effect on levels of plasma l-carnitine (LC). Methods: plasma levels of reactive oxygen species, superoxide dismutase (SOD), glutathion peroxidase (GSH-Px), catalase (CAT), total antioxidative capacity (T-AOC), and thiobarbituric acid reactive substances (TBARS) were measured in 34 patients (26 males and 8 females, mean age 47.7 ± 6.7 years) before and after craniotomy. Plasma levels of LC, acetyl-l-carnitine (ALC), and propionyl-l-carnitine (PLC) were also measured before and after the craniotomy. Results: the plasma concentrations of SOD, GSH-Px, CAT, and T-AOC within the first 4 h after craniotomy were lower than their baseline values (P < 0.05). There were no statistically significant differences in the mean plasma levels of SOD, GSH-Px, CAT, or T-AOC between the baseline and 24 h post-operative values. The level of TBARS at 4 h after the craniotomy was lower than the pre-operative level (P < 0.05), but the 24 h post-operative value was similar to the baseline concentration (P > 0.05). Plasma levels of LC, ALC, and PLC were lower after the craniotomy (P < 0.05), but these levels returned to the baseline levels 24 h after the operation. Conclusions: craniotomy and the associated procedures for surgery/anesthesia temporarily reduce antioxidant activity and plasma levels of l-carnitine.

scholarly journals Single Whole-Body Cryostimulation Procedure versus Single Dry Sauna Bath: Comparison of Oxidative Impact on Healthy Male Volunteers

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Paweł Sutkowy ◽  
Alina Woźniak ◽  
Paweł Rajewski
Keyword(s):  
Thiobarbituric Acid ◽  
Whole Body ◽  
Human Organism ◽  
Healthy Male ◽  
Thiobarbituric Acid Reactive Substances ◽  
Sod Activity ◽  
High And Low Temperatures ◽  
The Impact ◽  
Environmental Temperatures ◽  
Male Subjects

Exposure to extreme heat and cold is one of the environmental factors whose action is precisely based on the mechanisms involving free radicals. Fluctuations in ambient temperature are among the agents that toughen the human organism. The goal of the study was to evaluate the impact of extremely high (dry sauna, DS) and low (whole-body cryostimulation, WBC) environmental temperatures on the oxidant-antioxidant equilibrium in the blood of healthy male subjects. The subjects performed a single DS bath (n=10; 26.2 ± 4.6 years) and a single WBC procedure (n=15; 27.5 ± 3.1 years). In the subjects’ blood taken immediately before and 20 min after the interventions, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and the concentration of thiobarbituric acid reactive substances in erythrocytes (TBARSer) and blood plasma (TBARSpl) were determined. Single WBC and DS procedures induced an increase in the activity of SOD and GPx, as well as SOD and CAT, respectively. The SOD activity was higher after WBC than after DS. Extremely high and low temperatures probably induce the formation of reactive oxygen species in the organisms of healthy men and, therefore, disturb the oxidant-antioxidant balance.

scholarly journals Aging and its impact onthe quality of grafts: an experimental study in rats livers

2010 ◽  
Vol 47 (3) ◽  
pp. 297-300 ◽  
Author(s):  
Stela Maria Mota ◽  
Glauber Gasperin ◽  
Carlos Thadeu Cerski ◽  
Jarbas Rodrigues de Oliveira ◽  
Mário Reis Álvares-da-Silva
Keyword(s):  
Thiobarbituric Acid ◽  
Liver Weight ◽  
The Elderly ◽  
Elderly Group ◽  
Control Group ◽  
Thiobarbituric Acid Reactive Substances ◽  
Cold Ischemia ◽  
Liver Preservation ◽  
Uw Solution ◽  
The Impact

CONTEXT: There are consistent clues of worse results with grafts from older donors, especially in hepatitis C. University of Wisconsin (UW) solution is adopted for liver preservation, but other solutions are being studied, as fructose-1,6-bisphosphate (FBP). OBJECTIVE: To determinate the impact of aging of the donor on the cold ischemia injury in rat livers and compare UW and FBP. METHODS: Twenty male Wistar rats were studied - 10, aging 20 weeks: 5 to preservation with UW (C-UW) and 5, FBP (C-FBP); and other 10, aging 50 weeks: 5 to UW (E-UW) and 5 to FBP (E-FBP). Rats were anesthesized, submitted to hepatectomy, and graft was kept under 2-4ºC for 8 hours. Liquid samples were taken at 2, 4, 6, and 8 hours, to determine AST and LDH. At the end, in the liver tissue thiobarbituric acid reactive substances and catalase were determined. RESULTS: Average liver weight was similar between controls and the others (12.5 g ± 1.8 and 13.4 g ± 2.0). AST and LDH levels were higher in C-UW group (P<0.05). In the older group, there was a difference between UW and FBP preserved livers related to LDH, but not to AST. Thiobarbituric acid reactive substances were superior in control group than in the older one (P = 0.001). Catalase activity was similar between these groups (P = 0.11), but it was superior in UW preserved animals (P = 0.02). CONCLUSION: Livers from older rats were similar to the controls regarding cold ischemia injury in FBP group. Surprisingly, with UW solution there was less cold ischemia injury in the elderly group. When comparing both solutions, FBP provided significantly more protection than UW in the controls. There was a trend to FBP to being better than UW in the elderly group. Further studies with liver from older donors and ischemia and reperfusion are needed.

Sensory denervation of the kidney attenuates renovascular hypertension in the rat

1986 ◽  
Vol 250 (1) ◽  
pp. H82-H86 ◽  
Author(s):  
J. M. Wyss ◽  
N. Aboukarsh ◽  
S. Oparil
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Sensory Input ◽  
Sham Group ◽  
Left Renal Artery ◽  
Dorsal Rhizotomy ◽  
Afferent Nerves ◽  
Lower Blood ◽  
Sensory Denervation

To determine the role of the renal afferent nerves in the pathogenesis of one-kidney, one-clip renovascular hypertension, the renal afferent nerves were selectively lesioned by dorsal rhizotomy, a procedure that eliminates renal sensory input to the spinal cord but does not directly damage the sympathomotor innervation of the kidney. One week after denervation, the proximal left renal artery was clipped in denervated and sham control rats. Blood pressure of the sham group rose progressively over the next 5 wk, to 185 mmHg (systolic). In contrast, blood pressure of the denervated rats leveled off in the borderline hypertensive range, a level significantly lower than that of the sham group but significantly higher than that of non-clipped rats. In two further experiments the specificity of this effect was demonstrated. Lesion of the dorsal root nerves on the side of nephrectomy did not significantly lower blood pressure of non-clipped rats, and contralateral dorsal rhizotomy did not lower the blood pressure of clipped rats. These results demonstrate that the renal afferent nerves significantly contribute to one-kidney, one-clip renovascular hypertension in the rat.

Effects of renovascular hypertension on rat adrenal zona glomerulosa

1978 ◽  
Vol 36 (2) ◽  
pp. 582-583
Author(s):  
G. Mazzocchi ◽  
P. Rebuffat ◽  
C. Robba ◽  
P. Vassanelli ◽  
G. G. Nussdorfer
Keyword(s):  
Renovascular Hypertension ◽  
Left Kidney ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Ultrastructural Changes ◽  
Albino Rats ◽  
Left Renal Artery ◽  
Angiotensin System ◽  
And Control

It is well known that the rat adrenal zona glomerulosa steroidogenic activity is controlled by the renin-angiotensin system. The ultrastructural changes in the rat zona glomerulosa cells induced by renovascular hypertension were described previously, but as far as we are aware no correlated biochemical and morphometric investigations were performed.Twenty adult male albino rats were divided into 2 experimental groups. One group was subjected to restriction of blood flow to the left kidney by the application of a silver clip about the left renal artery. The other group was sham-operated and served as a control. Renovascular hypertension developed in about 10 days: sistolic blood pressure averaged 165 ± 6. 4 mmHg, whereas it was about 110 ± 3. 8 mmHg in the control animals. The hypertensive and control rats were sacrificed 20 days after the operation. The blood was collected and plasma renin activity was determined by radioimmunological methods. The aldosterone concentration was radioimmunologically assayed both in the plasma and in the homogenate of the left capsular adrenal gland.

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