scholarly journals Correction of retinal ischemic injuries by using non-selective imidazoline receptor agonists in the experiment

2019 ◽  
Vol 5 (4) ◽  
pp. 7-17
Author(s):  
Elena A. Levkova ◽  
Anton L. Pazhinsky ◽  
Sergey S. Lugovskoy ◽  
Anna A. Peresypkina ◽  
Victoria V. Bashuk ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sodium Salt ◽  
Potassium Salt ◽  
Ischemia Reperfusion ◽  
Retinal Blood Flow ◽  
Protective Effects ◽  
Doppler Flowmetry ◽  
Imidazoline Receptor ◽  
Receptor Agonists ◽  
Target Values

Introduction: Retinoprotective effects of non-selective imidazoline receptor agonists: potassium salt of С7070; sodium salt of С7070; С7070 processed with CO2 – were investigated in comparison with C7070 on the retinal ischemia-reperfusion model in rats. Materials and methods: The protective effects of the substances were evaluated by using ophthalmoscopy, laser Doppler flowmetry, electroretinography, histological and morphometric studies of retinal layers. Results and discussion: The most pronounced retinoprotective effect was observed in potassium salt of C7070 at a dose of 10 mg/kg, which expresses in approaching the normal eye fundus image, achieving the target values of the retinal blood flow, b/a coefficient, and reaching the norm values of morphometric indicators. A less pronounced protective effect was found in sodium salt of C7070 at a dose of 10 mg/kg, which expresses in a 71% decrease (p < 0.05) in semi-quantitative assessment of the eye fundus changes, an increase in the retinal blood flow level by 70.4% (p < 0.05), in b/a by 94% (p < 0.05) in comparison with the group without correction, and reaching the norm of the morphometric indicators. A retinoprotective effect of the substance C7070 processed with CO2 at a dose of 10 mg/kg is inferior to that of the sodium salt of C7070. Conclusion: The retinoprotective activity of the substances is expressed in descending order: potassium salt of С7070 (10 mg/kg) ≈ С7070 (50 mg/kg) > sodium salt of С7070 (10 mg/kg) > С7070 processed with CO2 (10 mg/kg) ≈ С7070 (10 mg/kg). Injections of glibenclamide leveled the neuroretinoprotective effects of the substances to varying degrees, which confirmed the participation of ATP-dependent potassium channels in the implementation of these effects.

Role of oxygen-derived free radicals in free growth retardation induced by ischemia-reperfusion in rats

1997 ◽  
Vol 272 (2) ◽  
pp. H701-H705 ◽  
Author(s):  
H. Ishimoto ◽  
M. Natori ◽  
M. Tanaka ◽  
T. Miyazaki ◽  
T. Kobayashi ◽  
...  
Keyword(s):  
Blood Flow ◽  
Free Radicals ◽  
Growth Retardation ◽  
Ischemia Reperfusion ◽  
Lipid Peroxides ◽  
Treated Group ◽  
Sprague Dawley ◽  
Doppler Flowmetry ◽  
Oxygen Derived Free Radicals ◽  
The Right

We investigated the involvement of oxygen-derived free radicals in the pathogenesis of the intrauterine growth retardation (IUGR) induced in Sprague-Dawley rats by ischemia-reperfusion. On day 17 of gestation, rats received saline, superoxide dismutase (SOD, 50,000 U/kg), catalase (CAT, 50,000 U/kg), or SOD + CAT subcutaneously 1 h before induction of 30 min of ischemia of the right uterine horn. On day 21 the placental level of lipid peroxides was significantly increased (P < 0.001 vs. sham-operated group) and IUGR was induced (P < 0.001 vs. left horn) in the saline-treated group n = 6). Pretreatment with SOD + CAT (n = 6) significantly inhibited the increase in placental lipid peroxides and prevented IUGR. The effect of ischemia-reperfusion on uterine blood flow, with or without pretreatment with radical scavengers, was investigated in separate experiments by laser-Doppler flowmetry. The induction of hypoperfusion 3 h after ischemia (blood flow -40 +/- 5%, n = 6, P < 0.05) was blocked by pretreatment with SOD + CAT (n = 6). Results indicate that oxygen-derived free radicals may be important in the development of postischemic uteroplacental hypoperfusion and of ischemia-reperfusion-induced IUGR in the rat.

P0522INHIBITING 15-PGDH PREVENTS ISCHEMIC RENAL INJURY BY A PGE2/EP4 SIGNALING PATHWAY MEDIATING VASODILATION, INCREASED RENAL BLOOD FLOW, AND INCREASED ADENOSINE/A2A RECEPTOR

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Byeong Woo KIm ◽  
Sun hee Kim ◽  
Ki beom Bae
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Adenosine A2a Receptor ◽  
Vehicle Group ◽  
Control Group ◽  
Protective Effects ◽  
A2a Receptor ◽  
Adenosine A2a

Abstract Background and Aims We demonstrate the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia reperfusion injury (IRI). AKI due to ischemic injury represents a significant clinical problem. Prostaglandin E2 (PGE2) is vasodilator in the kidney, but is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Method 10-week aged male C57/BL6 mice were randomly allocated to five groups (n=8 to 15 in each group): the sham-control group, sham-SW033291 group, IRI-vehicle group, IRI-indomethacin group and the IRI-SW033291 group. IRI were induced by clamping bilateral renal artery for 30 min followed by 24 hours of reperfusion. Vehicle, indomethacin, or SW033291 were intraperitoneally administered three times at 1 hour before, immediately after, and 12 hours after IRI. Renal function, histological changes, and renal blood flow were compared and the relevant parameters of oxidative stress and inflammation were detected. Results Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI histologic injury score and tubular apoptosis and markedly reduced biomarkers of renal injury that included BUN, creatinine, NGAL and KIM-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high mobility group box 1 (HMGB1), and malondialdehyde (MDA). Protective effects of SW033291 were mediated by PGE2 signaling as they could be blocked by pharmacologic inhibition of PGE2 synthesis or of the EP4 type PGE2 receptor. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 and of cyclic adenosine monophosphate (cAMP), along with other vasodilatory effectors including AMP, adenosine, and the adenosine A2A receptor (A2A). Protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Conclusion Inhibiting 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

α2-Adrenergic agonists protect against radiocontrast-induced nephropathy in mice

2008 ◽  
Vol 295 (3) ◽  
pp. F741-F748 ◽  
Author(s):  
F. T. Billings ◽  
Sean W. C. Chen ◽  
Mihwa Kim ◽  
Sang Won Park ◽  
Joseph H. Song ◽  
...  
Keyword(s):  
Blood Flow ◽  
Proximal Tubule ◽  
Adrenergic Receptor ◽  
Perioperative Period ◽  
Clinical Problem ◽  
Systemic Blood Pressure ◽  
Microvascular Endothelial Cell ◽  
Protective Effects ◽  
Receptor Agonists ◽  
Microvascular Endothelial

Radiocontrast nephropathy (RCN) is a common clinical problem for which there is no effective therapy. Utilizing a murine model, we tested the hypothesis that α2-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective α2-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. α2-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid (∼90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular α2-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but α2-agonists failed to preserve the viability of both cell types. We conclude that α2-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As α2-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.

Role of leukocytes in uterine hypoperfusion and fetal growth retardation induced by ischemia-reperfusion

2001 ◽  
Vol 280 (3) ◽  
pp. H1215-H1221 ◽  
Author(s):  
Kei Miyakoshi ◽  
Hitoshi Ishimoto ◽  
Osamu Nishimura ◽  
Shinji Tanigaki ◽  
Mamoru Tanaka ◽  
...  
Keyword(s):  
Blood Flow ◽  
Fetal Growth ◽  
Growth Retardation ◽  
Ischemia Reperfusion ◽  
Fetal Growth Retardation ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Doppler Flowmetry ◽  
Leukocyte Accumulation ◽  
Sprague Dawley Rats

We investigated leukocyte involvement in uterine hypoperfusion and intrauterine fetal growth retardation (IUGR) induced by ischemia-reperfusion (I/R) in Sprague-Dawley rats. On day 17 of gestation, leukocyte accumulation in the uterus and placenta subjected to 30 min of ischemia, followed by reperfusion, was assessed by measuring myeloperoxidase (MPO) activity. Uterine MPO activity was significantly higher after 1 h of reperfusion than it was before ischemia ( P < 0.05), without any increase in placental MPO activity. Immunohistochemical staining showed leukocyte accumulation in the uterus subjected to I/R. The effects of treatment with monoclonal antibodies against CD11a (WT1) and CD18 (WT3) at a dose of 0.8 mg/kg on uterine blood flow and IUGR were investigated. Laser-Doppler flowmetry demonstrated that uterine hypoperfusion at 2 h after ischemia (blood flow, −51.7 ± 1.2%; P < 0.01) was inhibited by WT1 and WT3 treatment. I/R-induced IUGR at full term ( P < 0.05 vs. nonischemic horn) was prevented by WT1 and WT3 treatment on day 17. These results indicate that leukocyte accumulation may play an important role in the pathogenesis of uterine hypoperfusion and IUGR induced by I/R in pregnant rats.

scholarly journals GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats

2016 ◽  
Vol 311 (2) ◽  
pp. G305-G312 ◽  
Author(s):  
Kaneto Tamura ◽  
Nobuhiko Hayashi ◽  
Joseph George ◽  
Nobuyuki Toshikuni ◽  
Tomiyasu Arisawa ◽  
...  
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Group Treatment ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vena Cava ◽  
Hepatic Tissue ◽  
Protective Effects ◽  
Hepatic Ischemia ◽  
Glutamyl Transpeptidase

Ischemia-reperfusion (IR) injury is a major clinical problem and is associated with numerous adverse effects. GGsTop [2-amino-4{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid] is a highly specific and irreversible γ-glutamyl transpeptidase (γ-GT) inhibitor. We studied the protective effects of GGsTop on IR-induced hepatic injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. Before clamping, saline (IR group) or saline containing 1 mg/kg body wt of GGsTop (IR-GGsTop group) was injected into the liver through the inferior vena cava. At 90 min of ischemia, blood flow was restored. Blood was collected before induction of ischemia and prior to restoration of blood flow and at 12, 24, and 48 h after reperfusion. All the animals were euthanized at 48 h after reperfusion and the livers were harvested. Serum levels of alanine transaminase, aspartate transaminase, and γ-GT were significantly lower after reperfusion in the IR-GGsTop group compared with the IR group. Massive hepatic necrosis was present in the IR group, while only few necroses were present in the IR-GGsTop group. Treatment with GGsTop increased hepatic GSH content, which was significantly reduced in the IR group. Furthermore, GGsTop prevented increase of hepatic γ-GT, malondialdehyde, 4-hydroxynonenal, and TNF-α while all these molecules significantly increased in the IR group. In conclusion, treatment with GGsTop increased glutathione levels and prevented formation of free radicals in the hepatic tissue that led to decreased IR-induced liver injury. GGsTop could be used as a pharmacological agent to prevent IR-induced liver injury and the related adverse events.

scholarly journals Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors

2020 ◽  
Vol 319 (6) ◽  
pp. F1054-F1066
Author(s):  
Hye Jung Kim ◽  
Sun-Hee Kim ◽  
Minjung Kim ◽  
HyungJoo Baik ◽  
Seok Ju Park ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Mobility ◽  
Kidney Injury ◽  
Clinical Problem ◽  
Protective Effects

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

scholarly journals Network Pharmacology Reveals the Mechanism of Activity of Tongqiao Huoxue Decoction Extract Against Middle Cerebral Artery Occlusion-Induced Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Vol 11 ◽  
Author(s):  
Si-peng Wu ◽  
Ning Wang ◽  
Li Zhao
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Functional Enrichment ◽  
Vehicle Group ◽  
Network Pharmacology ◽  
Protective Effects ◽  
Cerebral Ischemia Reperfusion

Several clinical therapies such as tissue repair by replacing injured tissues with functional ones have been reported; however, there is great potential for exploring traditional herbal-induced regeneration with good safety. Tongqiao Huoxue Decoction (TQHXD), a well-known classical traditional Chinese medicinal formula, has been widely used for clinical treatment of stroke. However, biological activity and mechanisms of action of its constituents toward conferring protection against cerebral ischemia-reperfusion (I/R) injury remain unclear. In this present study, we evaluated TQHXD quality using HPLC; then, it was screened for its potential active ingredients using a series of indices, such as their drug-likeness and oral bioavailability. Subsequently, we analyzed the potential mechanisms of TQHXD anti-I/R using gene ontology functional enrichment analyses. The network pharmacological approach enabled us to screen 265 common targets associated with I/R, indicating that TQHXD had remarkable protective effects on infarction volume, neurological function scores, and blood-brain barrier (BBB) injury. In addition, TQHXD significantly promoted the recovery of regional cerebral blood flow (rCBF) 7 days after reperfusion compared to rats in the vehicle group. Immunofluorescence results revealed a significantly higher CD34 expression in TQHXD-treated rats 7 days after reperfusion. TQHXD is not merely effective but eventually develops a secretory profile composed of VEGF and cerebral blood flow, a typical signature termed the angiogenesis-associated phenotype. Mechanistically, our data revealed that TQHXD (6 g/kg) treatment resulted in a marked increase in expression of p-focal adhesion kinase (FAK) and p-Paxillin proteins. However, Ki8751-mediated inhibition of VEGFR2 activity repealed its angiogenesis and protective effects and decreased both p-FAK and p-Paxillin protein levels. Taken together, these findings affirmed the potential of TQHXD as a drug for the management of stroke, which might be exerted by increasing the angiogenesis via the VEGF pathway. Therefore, these results provide proof-of-concept evidence that angiogenesis is a major contributor to TQHXD-treated I/R and that TQHXD is a promising traditional ethnic medicine for the management of this condition.

scholarly journals ET-1 plasma levels and ocular blood flow in retinitis pigmentosaThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 630-635 ◽  
Author(s):  
Mauro Cellini ◽  
Ernesto Strobbe ◽  
Corrado Gizzi ◽  
Emilio C. Campos
Keyword(s):  
Blood Flow ◽  
Plasma Levels ◽  
Color Doppler ◽  
Cold Pressor Test ◽  
Peak Systolic Velocity ◽  
Cold Pressor ◽  
Retinal Blood Flow ◽  
Doppler Imaging ◽  
Choroidal Blood Flow ◽  
Doppler Flowmetry

Retinitis pigmentosa (RP) is an inherited retinal disorder clinically characterized by a pale, waxy optic nerve head, attenuated retinal blood vessels, and bone spicule pigment in the retina. Hemodynamic studies have demonstrated that RP is associated with a reduction in the retinal and choroidal blood flow. Retinal hemodynamic impairment is also present in early stages of RP, and various hypotheses have been advanced as to the cause. The authors studied 20 patients, 12 males and 8 females, aged 26–42 years (mean 35.1 years) and affected by simplex RP. The patients had a visual acuity of 0.9 ± 0.1, visual field mean defect of –6.52 ± 3.58 dB, and b-wave electroretinogram amplitude of 260.08 ± 8.24 µV. An increase in plasma levels of endothelin-1 (ET-1) was found: 1.910 ± 0.317 pg/mL versus 1.180 ± 0.210 pg/mL in non-RP controls (p < 0.02). Moreover both an ocular and systemic vascular impairment was detected by means of color Doppler imaging and laser Doppler flowmetry performed during a cold pressor test. We found a correlation between the increase of ET-1 plasma levels in RP and the decrease of peak systolic velocity in the ophthalmic artery (p < 0.03) and in the posterior ciliary arteries (p < 0.006). It is thought that an increase of ET-1 and retinal oxygen levels in RP could lead to vasoconstriction and a decrease of the retinal blood flow, worsening the abiotrophic process.

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