scholarly journals Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 486
Author(s):  
Solène Marie ◽  
Irene Hernández-Lozano ◽  
Louise Breuil ◽  
Wadad Saba ◽  
Anthony Novell ◽  
...  
Keyword(s):  
Blood Flow ◽  
Biliary Excretion ◽  
Low Dose ◽  
Organic Anion ◽  
Liver Blood Flow ◽  
High Dose ◽  
Liver Uptake ◽  
Targeted Inhibition ◽  
Substrate Inhibitor

The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.

scholarly journals High dose intravenous aspirin, not low dose intravenous or oral aspirin, inhibits thrombus formation and stabilizes blood flow in experimental coronary vascular injury

1993 ◽  
Vol 21 (2) ◽  
pp. 502-510 ◽  
Author(s):  
Judith K. Mickelson ◽  
Paul T. Hoff ◽  
Jonathon W. Homeister ◽  
Joseph C. Fantone ◽  
Benedict R. Lucchesi
Keyword(s):  
Blood Flow ◽  
Vascular Injury ◽  
Low Dose ◽  
Thrombus Formation ◽  
High Dose ◽  
Oral Aspirin

Hemodynamic effects of recombinant human erythropoietin on the central nervous system after subarachnoid hemorrhage: reduction of microcirculatory impairment and functional deficits in a rabbit model

2008 ◽  
Vol 109 (6) ◽  
pp. 1155-1164 ◽  
Author(s):  
Amanda M. Murphy ◽  
Anargyros Xenocostas ◽  
Pria Pakkiri ◽  
Ting-Yim Lee
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Recombinant Human Erythropoietin ◽  
Low Dose ◽  
Saline Group ◽  
High Dose ◽  
Hemodynamic Effects ◽  
Neurological Outcomes ◽  
Human Erythropoietin

Object The authors investigated the hemodynamic effects of recombinant human erythropoietin (rhEPO) after subarachnoid hemorrhage (SAH) in rabbits. Methods The authors used male New Zealand White rabbits in this study divided into the following groups: SAH plus saline (16 rabbits), SAH plus low-dose rhEPO (16 rabbits; 1500 IU/kg on Day 0 and 500 IU/kg on Days 2 and 4), SAH plus high-dose rhEPO (10 rabbits; 1500 IU/kg on Days 0, 2, 4, and 6), and sham (6 rabbits). Computed tomography perfusion studies and CT angiography were performed for 1 hour after SAH on Day 0, and once each on Days 2, 4, 7, 9, and 16 after SAH. Assessments of neurological function and tissue histology were also performed. Results The mortality rate was significantly lower after rhEPO treatment (12%) than after saline treatment (44%) (p < 0.05). Neurological outcomes in the low-dose and high-dose rhEPO groups were better than in the saline group after SAH (p < 0.05), and the cerebral blood flow in the high-dose rhEPO group was greater than that in the saline group (p < 0.05). The mean transit time was significantly lower on Days 2 and 4 in the low-dose and high-dose rhEPO groups than in the saline group, but increased significantly on Day 7 in both groups (p < 0.05). The hematocrit increased significantly from baseline values in the high-dose and low-dose rhEPO groups on Days 4 and 7, respectively (p < 0.05). Conclusions Treatment with rhEPO after experimental SAH is associated with improved cerebral blood flow and microcirculatory flow as reflected by lower mean transit times. Improved tissue perfusion correlated with reduced mortality and improved neurological outcomes. Further investigation of the impact of increasing hematocrit on hemodynamic changes is needed.

scholarly journals M211. NEUROPROTECTIVE EFFECT OF SHI-ZHEN-AN-SHEN-TANG, A CHINESE HERB FORMULA ON MICE EXPOSED TO CUPRIZONE

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S216-S217
Author(s):  
Chao Ma ◽  
Yan Wu ◽  
Pei Chen ◽  
Yuan Jia ◽  
Dongqing Yin ◽  
...  
Keyword(s):  
Low Dose ◽  
Neuroprotective Effect ◽  
Chinese Herb ◽  
Large Body ◽  
High Dose ◽  
Neuregulin 1 ◽  
The Brain ◽  
Different Doses ◽  
Medium Dose

Abstract Background Our previous study indicated a therapeutic effect of Shi-Zhen-An-Shen-Tang (SZAST), a Chinese herb formula, on schizophrenia, but the related mechanism is unknown(citation). A large body of evidence suggests the important role of white matter of the brain in the pathophysiology of schizophrenia. This study was designed to evaluate the effect of SZAST on schizophrenia with demyelinated mice. Methods Male C57BL/6 mice were given mixed cuprizone (CPZ, a copper chelator, 0.2 %, w/w) rodent chow for six successive weeks to induce demyelination. During the last two weeks, mice were given an oral gavage of saline, or SZAST of three different doses (a low dose of 5.5g·kg-1·d-1, a medium dose of 8.24g·kg-1·d-1, or a high dose of 10.98 g·kg-1·d-1), or quetiapine, respectively. Behavioral tests were conducted after the last treatment. Meanwhile, the expression of myelin basic protein (MBP) and neuregulin-1(NRG1) in the brain was tested by immunohistochemistry staining or Western Blot. Results Mice exposed to CPZ for six weeks showed obvious schizophrenia-like behaviors, including lower nest-building activity, sensory gating activity, and higher locomotor activity. CPZ-fed mice also displayed a lower myelin density in the corpus callosum, hippocampus, and cerebral cortex and a reduction of MBP and NRG1 protein in the hippocampus compared with controls. Both quetiapine and SZAST significantly alleviated the abnormal schizophrenia-like behaviors and the impairment of myelin sheath in CPZ-fed mice, however, SZAST with medium dose showed better neuroprotective effect than the low dose or the high dose of SZAST. Furthermore, the expression of NRG1protein in the hippocampus was slightly, but not significantly increased in all SZAST-treated and quetiapine-treated groups. Discussion These results indicate that the neuroprotective effect of SZAST in demyelinated mice might partially relate to remyelination in the hippocampus in CPZ-fed mice.

Bronchial vasodilation by histamine in sheep: characterization of receptor subtype

1992 ◽  
Vol 72 (6) ◽  
pp. 2090-2098 ◽  
Author(s):  
G. H. Parsons ◽  
A. C. Villablanca ◽  
J. M. Brock ◽  
R. S. Howard ◽  
S. R. Colbert ◽  
...  
Keyword(s):  
Blood Flow ◽  
Low Dose ◽  
Receptor Subtype ◽  
High Dose ◽  
H1 Receptor ◽  
Receptor Antagonists ◽  
H2 Receptor Antagonists ◽  
Histamine Dihydrochloride ◽  
H2 Receptor ◽  
Arterial Blood

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% “low dose” or 5% “high dose”) before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal ammoniagenic response to chronic acid loading: role of glucocorticoids

1988 ◽  
Vol 254 (1) ◽  
pp. F134-F138 ◽  
Author(s):  
T. C. Welbourne ◽  
G. Givens ◽  
S. Joshi
Keyword(s):  
Production Rate ◽  
Low Dose ◽  
High Dose ◽  
Ammonium Excretion ◽  
Ammonia Production ◽  
Total Ammonia ◽  
High Doses ◽  
Reduced Rate ◽  
Acid Loading

Adrenalectomized (ADX) animals exhibit a blunted renal response to chronic acid loading. To determine whether this response truly reflects impaired renal ammoniagenesis from glutamine, urinary ammonium excretion was compared with acid intake in ADX, intact, and ADX rats supplemented with either a low dose (4 micrograms.100 g-1.day-1) or a high dose (40 micrograms.100 g-1.day-1) of triamcinolone. ADX rats consumed similar amounts of acid as did intact controls yet excreted only 37% of the load as ammonium; in contrast intact controls returned 86% and triamcinolone-supplemented animals returned 98 and 88% for low and high doses, respectively. Nor could the reduced ammonium excretion be attributed to increased renal venous release, since total ammonia production, the sum of renal venous and urine ammonium, was reduced to 49% of the intact controls; low- and high-dose triamcinolone restored and markedly increased the production rate. Underlying the impaired ammonia production rate in ADX rats was a reduced rate of glutamine extraction, 350 +/- 49 vs. 896 +/- 102 and 1,260 +/- 247 and 1,448 +/- 112 nmol.min-1.100 g-1 for intact and low and high doses, respectively. Unlike intact acidotic and glucocorticoid-supplemented ADX acidotic rats, glutamine extraction was disassociated from the delivered glutamine load consonant with the role of glucocorticoid in coupling cellular glutamine transport to its metabolic utilization.

Failure of oxygen radical scavengers to modify fatigue in electrically stimulated muscle

1991 ◽  
Vol 69 (10) ◽  
pp. 1470-1475 ◽  
Author(s):  
Ian Shrier ◽  
Sabah Hussain ◽  
Sheldon Magder
Keyword(s):  
Blood Flow ◽  
Dose Group ◽  
Gastrocnemius Muscle ◽  
Low Dose ◽  
Muscle Tension ◽  
Oxygen Radical ◽  
High Dose Group ◽  
High Dose ◽  
Partial Recovery ◽  
Radical Scavengers

We used in situ gastrocnemius muscle of anaesthetized dogs to test the hypothesis that O2 radical production during muscle contraction contributes to fatigue. Muscle tension was measured with a force transducer and blood flow was monitored with an electromagnetic flow probe. Muscle contractions were produced by stimulating the nerve for 15 min at 20 Hz, 12 trains/min, and a duty cycle of 0.25. Three groups of seven animals were given an infusion of 0.2 mL∙min−1 of either saline, low-dose oxygen radical scavengers (250 IU∙mL−1 superoxide dismutase, 640 IU∙mL−1 polyethylene glycol (PEG)-catalase, 0.25 mg∙mL−1 deferoxamine, and 0.1 mg∙mL−1 oxypurinol), or high-dose oxygen radical scavengers (3300 IU∙mL−1 uperoxide dismutase, 6600 IU∙mL−1 PEG-catalase, 2.5 mg∙mL−1 deferoxamine, and 0.1 mg∙mL−1 oxypurinol). Blood flow and vascular resistance of the gastrocnemius muscle during stimulation did not differ among groups. After 15 min of stimulation, the developed tension (represented as a percentage of initial tension developed) was 66 ± 7% in the saline treated group, 70 ± 6% in the low-dose group, and 70 ± 4% in the high-dose group. The change in tension during recovery was not significant in the control or low-dose groups. However, there was partial recovery in the high-dose group. In conclusion, in this preparation, oxygen radical scavengers did not delay the development of decreased muscle tension.Key words: muscle fatigue, oxygen free radicals, resistance, flow.

Role of α-Adrenoceptors in the Maintenance of Core Temperature in Humans

1995 ◽  
Vol 89 (3) ◽  
pp. 219-225
Author(s):  
Steven M. Frank ◽  
Nader El-Gamal ◽  
Srinivasa N. Raja ◽  
Peter K. Wu ◽  
Osama Afifi
Keyword(s):  
Blood Flow ◽  
Surface Temperature ◽  
Core Temperature ◽  
Heat Production ◽  
Skin Surface ◽  
High Dose ◽  
Skin Surface Temperature ◽  
Metabolic Heat ◽  
Males And Females

1. Although α-adrenoceptor antagonists have been shown to induce core hypothermia in animals, it is unclear whether the primary mechanism is increased heat loss or decreased heat production. Furthermore, studies have not been performed in humans to determine the role of α-adrenoceptors in the maintenance of core temperature. 2. α-Adrenoceptor blockade was achieved with three doses of phentolamine given by random assignment on three different study days in five male and five female healthy subjects. Core temperature, mean skin-surface temperature, fingertip capillary blood flow and metabolic heat production were measured. Dose—response curves were plotted for all measured variables, and males and females were compared to identify potential gender differences. 3. Core temperature decreased with all doses of phentolamine. At the completion of the phentolamine infusion, the decrease in core temperature was more significant with high-dose (0.3 ± 0.1°C, P = 0.03) and with medium-dose (0.2 ± 0.0deg;C, P = 0.05) phentolamine than with low-dose phentolamine (0.1 ± 0.0deg;C). The maximum core temperature decrease during the study was more significant with high dose (0.6 ± 1°C) than with medium (0.3 ± 1deg;C, P = 0.04) or low (0.3 ± 1°C, P = 0.005) doses. Mean skin-surface temperature was increased with all doses. Fingertip blood flow was increased (approximately 60% above baseline) with the medium and high doses, but was unchanged with the low dose. Total body oxygen consumption was unchanged regardless of dose. Although females had a higher core temperature at baseline, changes in core temperature, skin-surface temperature and fingertip blood flow were similar in males and females. 4. These findings suggest that α-adrenergic-antagonist-induced hypothermia results from a dose-dependent redistribution of heat from the core to the periphery, and not from a decrease in metabolic heat production. This leads us to conclude that baseline α-adrenergic ‘tone’ serves to maintain core temperature by constraining heat to the core thermal compartment.

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