scholarly journals THE CORRECTION OF ENDOTHELIAL DYSFUNCTION WITH THE HELP OF DISTANT ISCHEMIC AND PHARMACOLOGICAL PRECONDITIONING WITH THERMAL LOCAL ASPHYXIA OF KIDNEY

2018 ◽  
Vol 6 (2) ◽  
pp. 4-12
Author(s):  
O. I. Bratchikov ◽  
M. V. Pokrovskiy ◽  
V. V. Elagin ◽  
D. A. Kostina
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Ischemic Preconditioning ◽  
Conflicts Of Interest ◽  
Kidney Tissue ◽  
Phosphodiesterase Inhibitors ◽  
K Channels ◽  
Endothelium Dysfunction ◽  
Microcirculation Dysfunction ◽  
Pharmacological Preconditioning

This article contains the results of research of the endothelial dysfunction arising during the modeling of thermal local asphyxia of kidney and possibilities of their correction by distant ischemic and pharmacological preconditioning. The modeling of thermal local asphyxia of kidney is characterized by the disturbance of microcirculation and expression of eNOS in the kidney tissue. The usage of distant ischemic preconditioning and phosphodiesterase inhibitors type 5 sildenafil and tadalafil leads to pronounced correction of microcirculation dysfunction and activity of eNOS. During the modeling of thermal local asphyxia of kidney against endothelium dysfunction caused by ADMA-like L-NAME induced deficiency of nitric oxide more pronounced dysfunction of microcirculation and activity of eNOS are observed. The usage of distant ischemic and pharmacological preconditioning with the help of phosphodiesterase inhibitors type 5 in this type of pathology led to pronounced correction of microcirculation dysfunction and activity of eNOS. The injection of glibenclamide blocker of ATP – dependent K+ channels during the correction of the disturbance caused by the modeling of thermal local asphyxia of kidney with the help of distant ischemic and pharmacological preconditioning leads to the decrease of its efficiency.Disclosure: The study did not have sponsorship. The authors have declared no conflicts of interest.

Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

2020 ◽  
Vol 26 (30) ◽  
pp. 3633-3651 ◽  
Author(s):  
Javier Blanco-Rivero ◽  
Fabiano E. Xavier
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Phosphodiesterase Inhibitors ◽  
Developed Countries ◽  
Major Health Problem ◽  
Pde Inhibitors ◽  
Pharmaceutical Industries

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression

2005 ◽  
Vol 98 (1) ◽  
pp. 203-210 ◽  
Author(s):  
Christian K. Roberts ◽  
R. James Barnard ◽  
Ram K. Sindhu ◽  
Michael Jurczak ◽  
Ashkan Ehdaie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Protein Expression ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Kidney Tissue ◽  
High Fat ◽  
Caveolin 1 ◽  
Induced Hypertension ◽  
Nitric Oxide Deficiency

We tested whether consumption of a high-fat, high-sucrose (HFS) diet can affect endothelium-dependent relaxation, whether this precedes the development of diet-induced hypertension previously noted in this model, and whether it is mediated, in part, by changes in nitric oxide synthase (NOS) and/or NOS regulatory proteins. Female Fischer rats were fed either a HFS diet or standard low-fat, complex-carbohydrate chow starting at 2 mo of age for 7 mo. Vasoconstrictive response to KCl and phenylephrine was similar in both groups. Vasorelaxation to acetylcholine was significantly impaired in the HFS animals, and there were no differences in relaxation to sodium nitroprusside, suggesting that the endothelial dysfunction is due, at least in part, to nitric oxide deficiency. HFS consumption decreased protein expression of endothelial NOS in aorta, renal, and heart tissues, neuronal NOS in kidney, heart, aorta, and brain, and inducible NOS in heart and aorta. Caveolin-1 and soluble guanylate cyclase protein expression did not change, but AKT protein expression decreased in heart and aorta and increased in kidney tissue. Consumption of HFS diet raised brain carbonyl content and plasma hydrogen peroxide concentration and diminished plasma total antioxidant capacity. Because blood pressure, which is known to eventually rise in this model, was not as yet significantly elevated, the present data suggest that endothelial dysfunction precedes the onset of diet-induced hypertension. The lack of a quantitative change in caveolin-1 and soluble guanylate cyclase protein content indicates that alteration in these proteins is not responsible for the endothelial dysfunction. Thus nitric oxide deficiency combined with antioxidant/oxidant imbalance, appears to be a primary factor in the development of endothelial dysfunction in this model.

Decreased NO Bioavailability Leading to Endothelial Dysfunction in Children with ALL Results From Increased eNOS Inhibiting by Asymmetrical Dimethylarginine and May Be Associated with Increased Mortality

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5318-5318
Author(s):  
Julita Porwolik ◽  
Ewa Niedzielska ◽  
Adrian Doroszko ◽  
Alicja Piasecka-Grzeszek ◽  
Urszula Solska ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Conflicts Of Interest ◽  
Control Group ◽  
Healthy Children ◽  
Asymmetrical Dimethylarginine ◽  
Plasma Adma ◽  
No Bioavailability ◽  
Endothelial Nitric Oxide

Abstract Abstract 5318 Background Endothelial dysfunction worsens the prognosis in numerous severe diseases. Impaired vascular reactivity, increased procoagulative and proinflammatory action are commonly observed when the nitric oxide bioavailability is limited. Asymmetrical dimethylarginine (ADMA) is a competive inhibitor of the endothelial nitric oxide synthase (eNOS). ADMA is produced during proteolysis of methylated proteins, especially histones. The aim this study was to determine if ADMA may play important role in pathogenesis of endothelial dysfunction in children with ALL. Material and Methods N=14 children at age of 4–18 years with ALL treated with the ALLIC protocol were investigated. Plasma levels of the NO pathway metabolites (L-Arginine, ADMA) were analyzed at baseline, then during the 33rd and 78th day of protocol. The control group constituted of N=14, age-matched healthy children. Results Plasma ADMA levels were significantly higher in children with ALL at baseline as compared to the control group (1.92±0.42 vs. 0.56±0.1 ng/ml, p<0.05), and were significantly decreasing to 0.63±0.15ng/ml, p<0.05 following the steroid therapy. During the 78th day the ADMA levels were maintained at similar levels as compared to the 33rd day. Opposite trends were observed with the L-Arginine levels and the L-Arg/ADMA ratio reflecting the NO synthesis. L-Arg and L-Arg/ADMA ratio were significantly lower in children with ALL at baseline vs. control group (41.65±4.12vs.52.4±2.31pg/ml and 28.7±6.61vs.83.41±14.13, respectively, p<0.05). Moreover, the L-Arg/ADMA ratio at the 78th day was significantly higer in cases treated unsuccesfully in comparison with those who survived (88.1±21.3vs.43.0±10.2, p<0.05). Conclusions Decreased NO bioavailability in children with ALL at baseline results from the eNOS inhibiting by ADMA and may be associated with increased mortality. Disclosures: No relevant conflicts of interest to declare.

Reversal of hypertension and endothelial dysfunction in deoxycorticosterone-NaCl-treated rats by high-Ca2+ diet

1996 ◽  
Vol 270 (4) ◽  
pp. H1250-H1257
Author(s):  
H. Makynen ◽  
M. Kahonen ◽  
X. Wu ◽  
H. Wuorela ◽  
I. Porsti
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Methyl Ester ◽  
Endothelial Dysfunction ◽  
Wistar Rats ◽  
Normal Diet ◽  
Synthesis Inhibitor ◽  
K Channels ◽  
Arterial Relaxation

We tested the effect of high-Ca2+ diet on blood pressure and responses of mesenteric arterial rings in vitro in established deoxycorticosterone (DOC)-NaCl hypertension. Ca2+ supplementation (2.5%) of Wistar rats, which was commenced 8 wk after initiation of DOC-NaCl treatment (Ca(2+)-DOC group), reversed the development of hypertension, whereas in animals ingesting a normal diet (1.1% Ca2+; DOC group) blood pressure continued to rise until the end of the 12-wk study. In norepinephrine-precontracted arterial rings, relaxations to acetylcholine (ACh) and sodium nitroprusside were attenuated in the DOC group, but these responses were significantly improved by Ca2+ supplementation. The nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester, in the presence of diclofenac, totally abolished ACh-induced relaxations in the DOC group but only attenuated them in the Ca(2+)-DOC group. The remaining relaxation was further inhibited by apamin, an inhibitor of Ca(2+)-activated K+ channels, and practically abolished after blockade of ATP-dependent K+ channels by glyburide. Interestingly, when endothelium-dependent hyperpolarization was prevented using precontractions induced by KCl, no differences were found in relaxations to ACh between the groups. In conclusion, high-Ca(2+) diet effectively reduced blood pressure in DOC-NaCl hypertension and concomitantly enhanced arterial relaxation. Because the relaxations to ACh in the Ca(2+)-DOC group were augmented in the absence and presence of NO synthesis inhibition but not under conditions of prevented hyperpolarization, these enhanced relaxations could be attributed to promoted endothelium-dependent hyperpolarization in the Ca(2+)-supplemented animals.

Activated pericyte attenuates endothelial functions: nitric oxide – cGMP rescues activated pericyte-associated endothelial dysfunctions

2007 ◽  
Vol 85 (6) ◽  
pp. 709-720 ◽  
Author(s):  
Syamantak Majumder ◽  
K. P. Tamilarasan ◽  
Gopi Krishna Kolluru ◽  
Ajit Muley ◽  
C. Madhavan Nair ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Phosphodiesterase Inhibitor ◽  
Egg Yolk ◽  
No Production ◽  
Dependent Manner ◽  
Endothelium Dysfunction ◽  
Vascular Bed

Hepatic stellate cells are liver-specific pericytes and exist in close proximity with endothelial cells. The activation of liver pericytes is intrinsic to liver pathogenesis, and leads to endothelial dysfunction, including the low bioavailability of nitric oxide (NO). However, the role of nitric oxide in pericyte–endothelium cross-talk has not yet been elucidated. This work examines the cellular mechanism of action of NO in pericyte-mediated endothelial dysfunction. We used in vitro coculture and conditioned medium systems to study the effects of activated liver pericytes on endothelial function, and an egg yolk vascular bed model was used to study the effects of activated pericytes on angiogenesis. This study also demonstrates that activated pericytes attenuate the migration, proliferation, permeability, and NO production of endothelial cells. Our results demonstrate that activated pericytes restrict angiogenesis in egg yolk vascular bed models, and NO supplementation recovers 70% of the inhibition. Our results also demonstrate that supplementation with NO, sildenafil citrate (phosphodiesterase inhibitor), and 8-bromo-cGMP (cGMP analog) partially recovers activated-pericyte-mediated endothelium dysfunction. We conclude that NO–cGMP alleviates activated-pericyte-associated endothelial dysfunction, including angiogenesis, in a cGMP-dependent manner.

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