Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning

2004 ◽  
Vol 287 (6) ◽  
pp. H2746-H2753 ◽  
Author(s):  
Gentian Kristo ◽  
Yukihiro Yoshimura ◽  
Byron J. Keith ◽  
Randy M. Stevens ◽  
Salik A. Jahania ◽  
...  
Keyword(s):  
Myocardial Stunning ◽  
Receptor Agonist ◽  
Low Dose ◽  
Coronary Artery Occlusion ◽  
Receptor Activation ◽  
Artery Occlusion ◽  
Control Group ◽  
High Dose ◽  
Stroke Work

The purpose of this study was to determine whether the adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. Regional stunning was produced by 15 min of coronary artery occlusion and 3 h of reperfusion (RP) in anesthetized open-chest pigs. In acute protection studies, animals were pretreated with saline, low-dose AMP-579 (15 μg/kg iv bolus 10 min before ischemia), or high-dose AMP-579 (50 μg/kg iv at 14 μg/kg bolus + 1.2 μg·kg−1·min−1 for 30 min before coronary occlusion). The delayed preconditioning effects of AMP-579 were evaluated 24 h after administration of saline vehicle or high-dose AMP-579 (50 μg/kg iv). Load-insensitive contractility was assessed by measuring regional preload recruitable stroke work (PRSW) and PRSW area. Acute preconditioning with AMP-579 dose dependently improved regional PRSW: 129 ± 5 and 100 ± 2% in high- and low-dose AMP-579 groups, respectively, and 78 ± 5% in the control group at 3 h of RP. Administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.7 mg/kg) blocked the acute protective effect of high-dose AMP-579, indicating that these effects are mediated through A1 receptor activation. Delayed preconditioning with AMP-579 significantly increased recovery of PRSW area: 64 ± 5 vs. 33 ± 5% in control at 3 h of RP. In isolated perfused rat heart studies, kinetics of the onset and washout of AMP-579 A1 and A2a receptor-mediated effects were distinct compared with those of other adenosine receptor agonists. The unique nature of the adenosine agonist AMP-579 may play a role in its ability to induce delayed preconditioning against in vivo myocardial stunning.

scholarly journals Comparative Effects of Verapamil, Nicardipine, and Nitroglycerin on Myocardial Ischemia/Reperfusion Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Hitoshi Yui ◽  
Uno Imaizumi ◽  
Hisashi Beppu ◽  
Mitsuhiro Ito ◽  
Munetaka Furuya ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Control Group ◽  
Area At Risk ◽  
Group A

The aim of this experiment was to establish whether verapamil, nicardipine, and nitroglycerin have (1) infarct size-limiting effects and (2) antiarrhythmic effects inin vivorabbit hearts during ischemia/reperfusion. Rabbits received regional ischemia by 30 min of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion under ketamine and xylazine anesthesia. The animals were randomly assigned to the following 4 treatment groups: a control group, a verapamil group, a nicardipine group, and a nitroglycerin group. A continuous infusion of verapamil, nicardipine, or nitroglycerin was initiated 5 min prior to ischemia. Infarct size/area at risk decreased in verapamil, and nitroglycerin. The incidence of ischemia-induced arrhythmia decreased in nicardipine, verapamil and nitroglycerin. The incidence of reperfusion-induced arrhythmias decreased in verapamil and nitroglycerin. From the present experimental results, verapamil and nitroglycerin rather than nicardipine did afford significant protection to the heart subjected to ischemia and reperfusion in a rabbit model.

scholarly journals Sub-Chronic Toxicity Study of Hydroethanolic Leaf Extract of Telfairia Occidentalis Hook. F. (Cucurbitaceae) in Rats

2017 ◽  
Author(s):  
Abidemi J. Akindele ◽  
Joy A. Oladimeji-Salami ◽  
Ramon A. Oyetola ◽  
Daniel D. Osiagwu
Keyword(s):  
Leaf Extract ◽  
Chronic Toxicity ◽  
Biochemical Analysis ◽  
Low Dose ◽  
Oral Exposure ◽  
Control Group ◽  
High Dose ◽  
Telfairia Occidentalis ◽  
The Brain

Background: The leaf of Telfairia occidentalis Hook f. (Cucurbitaceae) is consumed in different parts of Nigeria because of the numerous nutritional and medicinal attributes ascribed to it. The sub-chronic toxicity of the hydroethanolic leaf extract of Telfairia occidentalis (TO) was investigated in this study. Methods: Rats in different groups were separately administered 80, 400 and 2000 mg/kg TO p.o. for 60 days. Animals were sacrificed and blood samples collected for haematological and biochemical analysis. Vital organs were harvested and evaluated for in vivo antioxidants and histopathological changes. Results: Results showed no significant changes in the weight of vital organs except in respect of the testes of the group treated with 2000 mg/kg extract which showed a significant (p<0.05) reduction in weight compared to the control group. There was a significant (p<0.01) increase in sperm motility and count of the group administered 80 mg/kg extract and a significant (p<0.001) reduction was observed at 2000 mg/kg. There were significant increases in the level of Hb and PCV at 80 and 2000 mg/kg of the extract. In respect of liver function parameters, a significant decrease in AST and ALT levels at doses of 400 and 2000 mg/kg relative to control was observed. A significant reduction (p<0.05) in the level of total cholesterol (400 mg/kg) and increase (p<0.05) in level of HDL (80-2000 mg/kg) compared to control was observed. There was also significant (p<0.05) increase in the level of MDA and significant (p<0.05) decrease in SOD level in the testes at 2000 mg/kg. Histopathological assessment of the testes revealed abnormality at this dose. These effects were reversed after 30 days of cessation of administration of TO. Conclusions: The findings showed that the hydroethanolic leaf extract of Telfairia occidentalis is relatively non-toxic on acute and sub-chronic exposure, with potential to elicit anti-anaemic effect, reduce the risk of atherosclerosis and cardiovascular disease, and enhance antioxidant status in the brain and liver. Although possibly beneficial at low dose, the extract could be harmful to the testes on prolonged oral exposure at high dose.

In Vivo Anti-Hypoxia and Anti-Fatigue Activities of Flavonoids from Bark of Eucommia ulmoides

2014 ◽  
Vol 675-677 ◽  
pp. 1608-1611 ◽  
Author(s):  
Jin Yang Lin ◽  
Zhuo Ying Zhang
Keyword(s):  
Low Dose ◽  
Forced Swimming Test ◽  
Saline Solution ◽  
Liver Glycogen ◽  
Control Group ◽  
High Dose ◽  
Eucommia Ulmoides ◽  
Swimming Time ◽  
Swimming Test

The present study was carried out to investigate anti-hypoxia and anti-fatigue activities of flavonoids from bark of Eucommia ulmoides (FEU) in mice. The animal were divided into four groups: control (C) group, low-dose FEU treated (LF) group, intermediate dose FEU treated (IF) group and high-dose FEU treated (HF) group. The treated groups received FEU (5, 15, 45mg/kg), while the control group received saline solution for 28 days. After 28 days, anti-hypoxia activity of FEU was assessed by the normobarie hypoxia test and anti-fatigue activity of FEU was assessed by the forced swimming test. The data showed that FEU could prolong survival time of oxygen deprivation and exhaustive swimming time by reducing BLA and BUN levels and increasing liver glycogen and muscle glycogen contents. Therefore, FEU had anti-hypoxia and anti-fatigue activities.

Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins

2003 ◽  
Vol 285 (4) ◽  
pp. H1650-H1659 ◽  
Author(s):  
Tsung-Ming Lee ◽  
Tsai-Fwu Chou
Keyword(s):  
Western Blot ◽  
Infarct Size ◽  
Dose Group ◽  
Low Dose ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Canine Model ◽  
Artery Occlusion ◽  
Border Zone ◽  
High Dose

Troglitazone, an antidiabetic thiazolidinedione, has been shown to have a scavenging effect on reactive oxygen species, which can modulate expression of connexin43. The study purpose was to evaluate whether troglitazone provides cardioprotection and to assess whether the cardioprotection is associated with an attenuated expression of connexin43 at the border of infarction in a canine model of acute myocardial infarction. Vehicle or troglitazone (1, 5, and 50 mg/kg; n = 14 for each group) was given intravenously 15 min before the coronary artery occlusion. Among the survivors, infarct size was significantly larger in the control than in the supplemented groups. There was a significantly lower infarct size in the high-dose group compared with that in the low-dose group (15 ± 7% vs. 23 ± 10% of the risk region in the low-dose group, P = 0.04). Reperfusion caused a significant elevation in superoxide anions as measured by lucigenin-derived chemiluminescence, which was significantly inhibited in animals treated with troglitazone. Connexin43 underwent dephosphorylation in response to ischemia-reperfusion measured by Western blot in control hearts at the border zone; these changes were significantly enhanced by troglitazone administration. Confocal microscopy confirmed the changes of junctional complexes. The magnitude of infarct size positively correlated with the magnitude of phosphorylated connexin43 expression assessed by Western blot analysis ( r = 0.73, P < 0.0001). This result demonstrated that the cardioprotective effect of troglitazone as an antioxidant may be associated with reduced phosphorylation of myocardial connexin43 protein.

Role of ET(A) and ET(B) receptors in endothelin-1-induced adrenal catecholamine secretion in vivo

1997 ◽  
Vol 272 (4) ◽  
pp. R1290-R1297 ◽  
Author(s):  
N. Yamaguchi
Keyword(s):  
High Performance ◽  
Low Dose ◽  
Dose Range ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Chromatography Method ◽  
Liquid Chromatography Method

The present study was designed to test whether endothelin (ET) A and/or B receptors in the adrenal medulla are functionally involved in ET-1-induced catecholamine (CA) release in anesthetized dogs. ET-1 was locally infused into the gland via the left adrenolumbar artery. Plasma CA in adrenal venous and aortic blood was determined by a high-performance liquid chromatography method. In the control group, the local infusion of ET-1 (0.5 microg, 0.4 microM) resulted in a significant increase in CA output. In the presence of a low dose of BQ-123 (5 microg, 16.4 microM), the ET-1-induced CA response was significantly attenuated by approximately 80%. With a high dose of BQ-123 (50 microg, 164 microM), the CA response was further blocked by approximately 95%. This inhibition was significantly greater than that obtained with the low dose of BQ-123. By contrast, a low dose of BQ-788 (5 microg, 15.1 microM) did not significantly affect the CA response. With a high dose of BQ-788 (50 microg, 151 microM), the CA response was only partially inhibited by approximately 70%. The results indicate that BQ-123 significantly inhibited ET-1-induced adrenal CA release in a dose-dependent manner. With the low doses, the CA response was markedly inhibited by BQ-123 but remained unchanged in the presence of BQ-788. Moreover, the high dose of BQ-123 virtually abolished the CA response, whereas BQ-788 failed to do so within the dose range tested. The present study suggests that the ET(A) receptor may play a predominant role in mediating the ET-1-induced CA secretion in the canine adrenal gland in vivo, although the possible involvement of the ET(B) receptor could not completely be excluded under the present experimental conditions.

Glycoprotein IIb/IIIa Receptor Antagonist Tirofiban Inhibits Thrombin Generation during Cardiopulmonary Bypass in Baboons

1999 ◽  
Vol 82 (07) ◽  
pp. 140-144 ◽  
Author(s):  
Ling Sun ◽  
Yugi Hiramatsu ◽  
Joseph H. Gorman ◽  
L. Henry Edmunds ◽  
A. Koneti Rao
Keyword(s):  
Cardiopulmonary Bypass ◽  
Thrombin Generation ◽  
Low Dose ◽  
Inhibitory Effect ◽  
Control Group ◽  
High Dose ◽  
Infusion Group ◽  
Dose Infusion

SummaryPlatelets play a major role in coagulation mechanisms and anti-GPIIb-IIIa antibodies inhibit tissue-factor induced thrombin generation in in vitro studies. Tirofiban, a nonpeptide selective glycoprotein (GP) IIb/IIIa antagonist, preserves platelet number and function during cardiopulmonary bypass (CPB) in baboons. We tested the hypothesis that platelet inhibition by tirofiban inhibits thrombin generation in vivo. Four groups of baboons (n = 7-12) were perfused for 60 min; all groups received heparin (300 units/kg). The controls received only heparin. The low dose (0.1 μg/kg/min) and high dose (0.3 μg/kg/min) infusion groups received tirofiban for 60 min before and 60 min during CPB. The bolus plus low dose infusion group received a 15 μg/kg bolus before starting CPB and a low dose infusion (0.1 mg/kg/min) only during CPB. At end of CPB, compared to control group (2.99 ± 0.36 nM), prothrombin fragment F1.2 levels were lower (p <0.05) in low dose infusion group (1.65 ± 0.14 nM, mean ± SE) and high dose infusion group (1.71 ± 0.19 nM), but not bolus plus infusion group (2.69 ± 0.49 nM); they remained significantly lower after protamine administration. At end of CPB, thrombin-antithrombin complex levels were lower in high dose infusion group (40.0 ± 11.2 ng/ml, p <0.05) compared to control group (76.2 ± 7.3 ng/ml). These studies indicate that tirofiban inhibits not only platelet aggregation but also thrombin generation in vivo during CPB, and that this effect is demonstrable even in the presence of intense heparin anticoagulation. They underscore the important inhibitory effect of GPIIb-IIIa antagonists on thrombin generation.

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

scholarly journals Low-dose sublingual immunotherapy compared to subcutaneous immunotherapy and conventional therapy in childhood asthma

2016 ◽  
Vol 44 (6) ◽  
pp. 243
Author(s):  
Ariyanto Harsono
Keyword(s):  
Childhood Asthma ◽  
Low Dose ◽  
Sublingual Immunotherapy ◽  
Disease Onset ◽  
Ethics Committee ◽  
Subcutaneous Immunotherapy ◽  
Control Group ◽  
High Dose ◽  
Treat Ment ◽  
Group A

Background Evidence begin to accumulate that high-dose sub-lingual immunotherapy (SLIT) is as effective as subcutaneousimmunotherapy (SIT) in the treatment of childhood asthma.Since the capacity of sublingual area is similar whether the doseis high or low, the efficacy of low dose may be important to bestudied.Objective To investigate the efficacy of low-dose sublingual im-munotherapy in the treatment of childhood asthma.Methods Parents signed informed consent prior to enrollment,after having received information about the study. Patients weremoderate asthma aged 6-14 years with disease onset of lessthan 2 years before the commencement of the study and peakexpiratory flow rate (PEFR) variability of more than 15%. Pa-tients were randomly allocated into group A, B, and C whoreceived subcutaneous immunotherapy, low-dose sublingualimmunotherapy, and conventional asthma therapy, respectively.Randomization was stratified into two strata according to agei.e., 6-11 years or 11-14 years. Patients of each stratum wererandomized in block of three for each group. At the end of threemonths, lung function tests were repeated. The primary outcomewas PEFR variability at the end of the study. The study wasapproved by the Ethics Committee of Soetomo HospitalSurabaya.Results Distribution of variants as represented by sex, age,eosinophil count, and total IgE concentration were normal inthe three groups. PEFR variability decreased significantly from16.97+0.81 to 8.50+5.08 and 17.0+0.87 to 8.40+4.72 in groupreceiving SIT and SLIT, respectively (p<0.05), but decreasednot significantly from 17.00+0.83 to 10.82+0.5.41 in control group(p>0.05).Conclusion Low-dose SLIT is as efficacious as SIT in the treat-ment of moderate asthma in children

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

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