scholarly journals Identification of Potential Radiation Responsive Metabolic Biomarkers in Plasma of Rats Exposed to Different Doses of Cobalt-60 Gamma Rays

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582097957
Author(s):  
Hua Zhao ◽  
Cong Xi ◽  
Mei Tian ◽  
Xue Lu ◽  
Tian-Jing Cai ◽  
...  
Keyword(s):  
Gamma Rays ◽  
Dose Response ◽  
Area Under The Curve ◽  
Rat Plasma ◽  
Dose Assessment ◽  
Sprague Dawley ◽  
Targeted Metabolomics ◽  
Response Curves ◽  
Sprague Dawley Rats ◽  
Metabolic Biomarkers

Metabolomics has great potential to process accessible biofluids through high-throughput and quantitative analysis for radiation biomarker screening. This study focused on the potential radiation responsive metabolites in rat plasma and the dose-response relationships. In the discovery stage, 20 male Sprague–Dawley rats were exposed to 0, 1, 3 and 5 Gy of cobalt-60 gamma rays at a dose rate of 1 Gy/min. Plasma samples were collected at 72 h after exposure and analyzed using liquid chromatography mass spectrometry based on non-targeted metabolomics. In the verification stage, 50 additional rats were exposed to 0, 1, 2, 3, 5 and 8 Gy of gamma rays. The concentrations of candidate metabolites were then analyzed using targeted metabolomics methods. Fifteen candidate radiation responsive metabolites were identified as potential radiation metabolite biomarkers. Metabolic pathways, such as linoleic acid metabolism and glycerophospholipid metabolism pathways, were changed after irradiation. Six radiation responsive metabolites, including LysoPC(20:2), LysoPC(20:3), PC(18:0/22:5), L-palmitoylcarnitine, N-acetylornithine and butyrylcarnitine, had good dose-response relationships ( R 2 > 0.80). The area under the curve of the panel of the 6 radiation responsive metabolites was 0.923. The radiation exposure metabolomics biomarkers and dose-response curves may have potential for rapid dose assessment and triage in nuclear and radiation accidents.

Effects of PAF on isolated rat airways perfused with blood-free solution

1991 ◽  
Vol 260 (4) ◽  
pp. L260-L267
Author(s):  
N. M. Munoz ◽  
C. F. Kirchhoff ◽  
M. E. Strek ◽  
R. N. Blumenthal ◽  
A. R. Leff
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Platelet Activating Factor ◽  
Tissue Perfusion ◽  
Sprague Dawley ◽  
Response Curves ◽  
Peripheral Airways ◽  
Sprague Dawley Rats ◽  
Lung Resistance ◽  
Prior Administration

We examined the mechanism of constriction and muscarinic augmentation of contraction of airway smooth muscle caused by platelet-activating factor (PAF) in airways from 55 Sprague-Dawley rats perfused through the isolated bronchial circulation (BC) and pulmonary circulation (PC) and isometrically in tissue perfusion chambers. Dose-response curves were generated cumulatively by infusing 10(-10) to 10(-7) mol PAF dissolved in Krebs-Henseleit solution buffer containing 4% bovine serum albumin into the BC or PC. The efficacy of PAF in central airways (BC) was approximately twofold greater in increasing lung resistance (RL) than for more peripheral airways perfused by the PC (P less than 0.05). Tachyphylaxis was demonstrated in both BC and PC for preparations in which a second PAF dose-response curve was generated. Bolus injection of 10(-6) mol of the PAF antagonist, CV-6209, plus 10(-7) mol PAF caused 81% reversal of the maximal BC response. The same dose of CV-6209 reversed the response to PAF in the PC by 99.2%. Initial administration of 10(-6) mol CV-6209 with PAF prevented completely contraction elicited by PAF in the BC and PC. Concentration-response studies also were generated isometrically in tissue perfusion chambers from 64 tracheal smooth muscle strips. Maximal contraction elicited by 10(-6) M PAF was blocked completely with 10(-6) M CV-6209. In separate studies, addition of 10(-6) mol CV-6209 to the BC perfusate caused 93% blockade of the RL response to PAF and 100% inhibition when administered in the PC. Prior administration of PAF caused two- to fourfold augmentation of the contractile response to acetylcholine (ACh) within the same preparation; in the presence of CV-6209, the response to ACh was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking

2018 ◽  
Vol 33 (1) ◽  
pp. 132-144
Author(s):  
Tracey A Larson ◽  
Casey E O’Neill ◽  
Michaela P Palumbo ◽  
Ryan K Bachtell
Keyword(s):  
Dose Response ◽  
Extinction Training ◽  
Schedules Of Reinforcement ◽  
Sprague Dawley ◽  
Self Administration ◽  
Caffeine Consumption ◽  
Adult Rats ◽  
Sprague Dawley Rats ◽  
Cocaine Seeking ◽  
Administration Procedure

Background: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. Aim: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Methods: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62–82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Results: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. Conclusions: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.

Glutathione enhances endothelium-mediated control of coronary vascular resistance via a ROS- and NO intermediate-dependent mechanism

2012 ◽  
Vol 113 (2) ◽  
pp. 246-254 ◽  
Author(s):  
Andrew S. Levy ◽  
Chris Vigna ◽  
James W. E. Rush
Keyword(s):  
Vascular Resistance ◽  
Dose Response ◽  
Vascular Function ◽  
Soluble Guanylate Cyclase ◽  
Threshold Concentration ◽  
Coronary Vascular Resistance ◽  
Sprague Dawley ◽  
Response Curves ◽  
Physiological Relevance ◽  
Dependent Mechanism

The purpose of this investigation was to determine the effects of acute physiological GSH administration on endothelium-mediated reduction in coronary vascular resistance (CVR) using isolated perfused Sprague-Dawley rat hearts. A dose-response curve to GSH was conducted to determine a threshold concentration of GSH. We demonstrate that 30 μM GSH was sufficient to reduce CVR, and maximal dilation was achieved with 1 mM. In subsequent experiments, GSH was administered at concentrations of 0 [control (CON)], 1 μM, or 10 μM (GSH10), and dose-response curves to the endothelial agonist bradykinin (BK) were constructed. These GSH concentrations were chosen because of the physiological relevance and because the effects of GSH on BK action could be assessed independent of baseline differences in CVR. Sensitivity to BK (EC50) was enhanced in GSH10 vs. CON ( P < 0.05). This enhancement remained in the presence of nitric oxide (NO) synthase inhibition l-ωnitro-l-arginine (lNAME) and/or soluble guanylate cyclase (sGC) inhibition. Treatment with 4-hydroxy (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPOL) enhanced the sensitivity to BK in CON, similar to the effects of GSH10 and GSH10 + TEMPOL. However, the GSH10-dependent enhancement of EC50 observed in the presence of lNAME did not occur in the presence of lNAME + TEMPOL or in the presence of lNAME + sGC inhibition and NO scavenging. Collectively, these results suggest that GSH enhances BK-mediated dilation and reduction in CVR through an antioxidant-dependent mechanism that involves a NO intermediate but is unrelated to acute production of NO and GC-dependent effects of NO. These results suggest a mechanism whereby physiologically relevant levels of GSH modulate the endogenous reactive oxygen species and NO control of endothelium-dependent coronary vascular function.

Adrenomedullin microinjection into the area postrema increases blood pressure

1997 ◽  
Vol 272 (6) ◽  
pp. R1698-R1703 ◽  
Author(s):  
M. A. Allen ◽  
P. M. Smith ◽  
A. V. Ferguson
Keyword(s):  
Blood Pressure ◽  
Area Postrema ◽  
Area Under The Curve ◽  
Physiological Role ◽  
Cardiovascular Responses ◽  
Hypotensive Effect ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Brain Site

Adrenomedullin (ADM) circulates in the blood at concentrations comparable to other vasoactive peptides with established roles in cardiovascular regulation. Intravenously administered ADM produces a clear hypotensive effect, whereas intracerebroventricular microinjections result in increases in blood pressure (BP). Recently, we demonstrated that ADM influences neurons of the area postrema (AP), a central nervous system site implicated in cardiovascular control. However, to address directly the physiological significance of the actions of ADM at the AP, an in vivo microinjection study was undertaken. ADM, at two concentrations (1 and 10 microM), in volumes of 50, 100, and 200 nl, was microinjected into the AP or NTS of 21 urethan-anesthetized male Sprague-Dawley rats. Microinjection of 10 microM ADM (100 nl) resulted in significant transient (2-5 min) increases in BP [120 s area under the curve (AUC): 684.3 +/- 268.6 mmHg/s (P < 0.05)], and heart rate (HR) [AUC: 12.5 +/- 4.5 beats/min (P < 0.05)]. The lower concentration of ADM (1 microM) had no effect on either BP (179.1 +/- 143.6 mmHg/s) or HR (0.8 +/- 2.6 beats/min). ADM was also microinjected into the immediately adjacent nucleus of the solitary tract, where it was found to be without effect on either BP or HR. This study demonstrates, for the first time, a physiological role for ADM acting at a specific brain site, the AP, to produce significant cardiovascular responses.

Subchronic Dose-Response Study of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Female Sprague-Dawley Rats

1995 ◽  
Vol 132 (1) ◽  
pp. 1-13 ◽  
Author(s):  
A.P.J.M. Vanbirgelen ◽  
J. Vanderkolk ◽  
K.M. Fase ◽  
I. Bol ◽  
H. Poiger ◽  
...  
Keyword(s):  
Dose Response ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tetrachlorodibenzo P Dioxin ◽  
Dose Response Study

17β-Estradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage

2007 ◽  
Vol 292 (1) ◽  
pp. H245-H250 ◽  
Author(s):  
Zheng F. Ba ◽  
Ailing Lu ◽  
Tomoharu Shimizu ◽  
László Szalay ◽  
Martin G. Schwacha ◽  
...  
Keyword(s):  
Control Level ◽  
No Synthase ◽  
Sprague Dawley ◽  
Response Curves ◽  
Endothelin 1 ◽  
Sprague Dawley Rats ◽  
17Β Estradiol ◽  
Synthase Inhibitor

Although endothelin-1 (ET-1) induces vasoconstriction, it remains unknown whether 17β-estradiol (E2) treatment following trauma-hemorrhage alters these ET-1-induced vasoconstrictive effects. In addition, the role of the specific estrogen receptor (ER) subtypes (ER-α and ER-β) and the endothelium-localized downstream mechanisms of actions of E2 remain unclear. We hypothesized that E2 attenuates increased ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-β-mediated pathway. To study this, aortic rings were isolated from male Sprague-Dawley rats following trauma-hemorrhage with or without E2 treatment, and alterations in tension were determined in vitro. Dose-response curves to ET-1 were determined, and the vasoactive properties of E2, propylpyrazole triol (PPT, ER-α agonist), and diarylpropionitrile (DPN, ER-β agonist) were determined. The results showed that trauma-hemorrhage significantly increased ET-1-induced vasoconstriction; however, administration of E2 normalized ET-1-induced vasoconstriction in trauma-hemorrhage vessels to the sham-operated control level. The ER-β agonist DPN counteracted ET-1-induced vasoconstriction, whereas the ER-α agonist PPT was ineffective. Moreover, the vasorelaxing effects of E2 were not observed in endothelium-denuded aortic rings or by pretreatment of the rings with a nitric oxide (NO) synthase inhibitor. Cyclooxygenase inhibition with indomethacin had no effect on the action of E2. Thus, E2 administration attenuates ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-β-mediated pathway that is dependent on endothelium-derived NO synthesis.

scholarly journals Pharmacokinetic Comparison of Isoalantolactone and Alantolactone in Rats after Administration Separately by Optimization of an UPLC-MS2Method

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Renjie Xu ◽  
Mengyue Wang ◽  
Ying Peng ◽  
Xiaobo Li
Keyword(s):  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Rat Plasma ◽  
Sprague Dawley ◽  
Ionization Source ◽  
Fragment Ions ◽  
Sprague Dawley Rats ◽  
Liquid Chromatography Tandem Mass ◽  
Positive Ion

Isoalantolactone and alantolactone are two major active ingredients that are present in many medicinal plants. In this study, a sensitive and rapid ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for determination of the two compounds in rat plasma, separately. In this method, an electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring (MRM) was selected for quantification using target fragment ions 233.2→187.1 for isoalantolactone (alantolactone) and 245.1→189.1 for internal standard (IS). Retention time of the lactones and IS was within 3.0 min. Further calibration suggested a linear regression can be calculated within 2.5–500 ng/mL for isoalantolactone and 4–500 ng/mL for alantolactone. This method was used to compare the pharmacokinetic characteristics of isoalantolactone and alantolactone at a single dose of 5 mg/kg into male Sprague-Dawley rats by intravenous administration separately. The levels oft1/2, Kel, CL,Cmax, and AUC were significantly increased in the alantolactone group compared to isoalantolactone. These results suggested that isoalantolactone was distributed and eliminated more rapidly than alantolactone in rats when administered, respectively.

Modulation of in vivo 3-deoxyglucosone levels

2003 ◽  
Vol 31 (6) ◽  
pp. 1433-1437 ◽  
Author(s):  
T.R. Brown ◽  
B. Su ◽  
K.A. Brown ◽  
M.A. Schwartz ◽  
A.M. Tobia ◽  
...  
Keyword(s):  
Fold Increase ◽  
Rat Plasma ◽  
Diabetic Rat ◽  
Kidney Tubules ◽  
Sprague Dawley ◽  
Birth Rates ◽  
Fischer 344 ◽  
Sprague Dawley Rats ◽  
Eker Rat

Fructoselysine 3-phosphate is synthesized in vivo by the recently discovered fructoseamine-3-kinase (F3K) from fructoselysine and ATP and decomposes to lysine, Pi and 3-deoxyglucosone (3DG). This pathway appears to dominate 3DG production in vivo, making it possible to modulate 3DG levels by stimulating or inhibiting the reaction. Present inhibitors are non-reacting substrate analogues with relatively high Ki values and can inhibit F3K sufficiently in vivo to reduce 3DG in diabetic rat plasma by approx. 50%. Stimulation of the F3K pathway by feeding glycated casein causes an increase of 10–20-fold in plasma levels of 3DG and 3-fold in kidney tubules. Consequences of this increase were studied in two systems: the Eker rat, a model of susceptible kidney tubules; and birth rates in two rat strains. In both cases substantial pathological effects were observed. In the Eker rats, an approx. 3-fold increase in kidney lesions was observed (P<0.00001). In both Fischer 344 and Sprague–Dawley rats, birth rates were reduced by 56% (P<0.0001) and 12% (P<0.015) respectively. These results suggest that inhibition of F3K is a promising new therapeutic target for diabetic complications, as well as other 3DG-dependent pathologies.

scholarly journals Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

2021 ◽  
Author(s):  
Marianne Skov-Skov Bergh ◽  
Inger Lise Bogen ◽  
Nancy Garibay ◽  
Michael H. Baumann
Keyword(s):  
High Performance ◽  
Parent Drug ◽  
Rat Plasma ◽  
Male Rats ◽  
Sprague Dawley ◽  
Limit Of Quantification ◽  
Sprague Dawley Rats ◽  
Liquid Chromatography Tandem Mass ◽  
Blood Specimens

Abstract Background Illicitly manufactured fentanyl and its analogs are a major driving force behind the ongoing opioid crisis. Cyclopropylfentanyl is a fentanyl analog associated with many overdose deaths, but limited knowledge is available about its pharmacology. In the present study, we developed a bioanalytical method for the determination of cyclopropylfentanyl and its main metabolite cyclopropylnorfentanyl and evaluated pharmacokinetic-pharmacodynamic relationships in rats. Method An ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for determination of cyclopropylfentanyl and cyclopropylnorfentanyl in rat plasma. Male Sprague–Dawley rats fitted with jugular catheters and temperature transponders received cyclopropylfentanyl (30, 100, and 300 μg/kg) or saline subcutaneously. Blood specimens were withdrawn over an 8-h time period, along with measurements of pharmacodynamic endpoints. Results The analytical method was validated, and both analytes exhibited a low limit of quantification (15 pg/mL). Cyclopropylfentanyl caused dose-related increases in hot plate latency (ED50 = 48 µg/kg) and catalepsy (ED50 = 87 µg/kg) and produced long-lasting hypothermia at the highest dose. Plasma cyclopropylfentanyl rose rapidly in a dose-related fashion, reaching maximal concentration (Cmax) after 15–28 min, whereas metabolite Cmax occurred later at 45–90 min. Cyclopropylfentanyl Cmax values were similar to concentrations measured in non-fatal intoxications in humans; however, differences in parent drug: metabolite ratio indicated possible interspecies variance in metabolism. Conclusion Our study shows that cyclopropylfentanyl produces typical opioid-like effects in male rats. Cyclopropylfentanyl displays much greater analgesic potency when compared to morphine, suggesting that cyclopropylfentanyl poses increased overdose risk for unsuspecting users.

scholarly journals Pharmacokinetics of ligustroflavone in rats and tissue distribution in mice by UPLC–MS/MS

2020 ◽  
Vol 32 (2) ◽  
pp. 102-106 ◽  
Author(s):  
Quan Zhou ◽  
Zhiguang Zhang ◽  
Peiwu Geng ◽  
Bingge Huang ◽  
Xianqin Wang ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Intraperitoneal Administration ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Mouse Tissues ◽  
Extensive Metabolism ◽  
Liquid Chromatography Tandem Mass ◽  
Group 1

An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for quantification of ligustroflavone, which was then applied in pharmacokinetics study in rat and tissue distribution in mouse. Twelve male Sprague Dawley rats were used for pharmacokinetics after intravenous (2 or 8 mg/kg) administration of ligustroflavone, six rats for each dose. Twenty-five mice were randomly divided into 5 groups (5 mice for each group, 1 group for each time point) and received 16 mg/kg ligustroflavone via intraperitoneal administration. The linear range of the calibration curve was over 2–2000 ng/mL for ligustroflavone in rat plasma and mouse tissues. The intra-day and inter-day precision expressed in % RSD were less than 14%, and the accuracy was between 88.5% and 108.4%. The tissue distribution results indicated that ligustroflavone diffuses rapidly and widely into major organs. The level of ligustroflavone was highest in the mouse liver, followed by the kidney, spleen, and lung. The overwhelming accumulation in the liver indicated that the liver was responsible for the extensive metabolism.

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