Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.

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Distribution of kallikrein-binding protein mRNA in kidneys and difference between SHR and WKY rats

AJP Renal Physiology ◽

10.1152/ajprenal.1994.267.2.f325 ◽

1994 ◽

Vol 267 (2) ◽

pp. F325-F330 ◽

Cited By ~ 1

Author(s):

T. Yang ◽

Y. Terada ◽

H. Nonoguchi ◽

M. Tsujino ◽

K. Tomita ◽

...

Keyword(s):

Blot Analysis ◽

Binding Protein ◽

Collecting Duct ◽

Cortical Collecting Duct ◽

Sprague Dawley ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Sd Rats ◽

Medullary Collecting Duct ◽

Wistar Kyoto

We investigated kallikrein-binding protein (KBP) mRNA distribution in the kidney of Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHR), and Wistar-Kyoto strain (WKY) rats. Northern blot analysis revealed that KBP mRNA was located mainly in the medulla and with lower amounts in SHR than in WKY rats. KBP mRNA in microdissected nephron segments was detected by reverse transcription and polymerase chain reaction (RT-PCR) followed by Southern blot analysis. In SD rats, the most abundant signals were consistently found in inner medullary collecting duct (IMCD), with small amounts in outer medullary collecting duct, proximal convoluted tubule, and glomerulus. No signals were found in connecting tubule and cortical collecting duct. The nephron distribution of KBP mRNA was similar in WKY and SD rats. Only a small amount of signal was found, however, in IMCD of SHR. In conclusion, 1) KBP mRNA was predominantly distributed in the medullary segments of the distal nephron, downstream from the known kallikrein activity site in the collecting duct, and 2) KBP mRNA expression was significantly decreased in the kidney of SHR.

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Endorphinergic mechanism in the central cardiovascular and analgesic effects of clonidine

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-255 ◽

1987 ◽

Vol 65 (8) ◽

pp. 1624-1632 ◽

Cited By ~ 26

Author(s):

G. Kunos ◽

R. Mosqueda-Garcia ◽

J. A. Mastrianni ◽

F. V. Abbott

Keyword(s):

Receptor Antagonist ◽

Arcuate Nucleus ◽

Monosodium Glutamate ◽

Opiate Receptors ◽

Cardiovascular Effects ◽

Male Rats ◽

Sprague Dawley ◽

Wky Rats ◽

Sd Rats ◽

Wistar Kyoto

In urethane-anesthetized male rats, injection of 5 nmol clonidine into the nucleus of the solitary tract (NTS) causes hypotension and bradycardia. These effects are greater in spontaneously hypertensive rats (SHR) and normotensive Sprague–Dawley (SD) rats than in normotensive Wistar–Kyoto (WKY) rats. The effects of clonidine are stereoselectively inhibited by 100 ng intra-NTS naloxone in SHR and SD but not in WKY rats. In SHR, the effects of clonidine are also inhibited by intra-NTS administration of ICI 174864 (a δ-receptor antagonist) but not by β-funaltrexamine (a μ-receptor antagonist), while in SD rats only the μ- and not the δ-antagonist was effective. Neonatal treatment of SHR with monosodium glutamate (MSG) reduced the β-endorphin content of the arcuate nucleus and the NTS, reduced the cardiovascular effects of clonidine, and abolished their naloxone sensitivity. MSG treatment of newborn WKY reduced the β-endorphin content of the arcuate nucleus but not the NTS and did not affect the responses to clonidine. Measurement of pain sensitivity by the formalin test indicated that clonidine was more potent as an analgesic in SHR and SD than in WKY rats, and its effect was inhibited by naloxone (2 mg/kg i.p.) in the former two strains but not in WKY. It is proposed that a naloxone-sensitive component of the cardiovascular effects of clonidine is due to release of a β-endorphin-like opioid from the NTS, and that this mechanism is present in SHR and SD but not in WKY rats. The opiate receptors mediating the effects of the opioid appear to be of the μ-subtype in SD rats and of the δ-subtype in SHR. The results also support a close relationship between central cardiovascular and pain regulatory mechanisms.

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Gastroparesis and lipid metabolism-associated dysbiosis in Wistar-Kyoto rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00008.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. G62-G72 ◽

Cited By ~ 15

Author(s):

J. E. Dalziel ◽

Karl Fraser ◽

Wayne Young ◽

Catherine M. McKenzie ◽

Shalome A. Bassett ◽

...

Keyword(s):

Small Intestine ◽

Liquid Chromatography ◽

Gastric Emptying ◽

Delayed Gastric Emptying ◽

Wky Rats ◽

Sd Rats ◽

Wistar Kyoto Rat ◽

Rat Strain ◽

Gi Transit ◽

Wistar Kyoto

Altered gastric accommodation and intestinal morphology suggest impaired gastrointestinal (GI) transit may occur in the Wistar-Kyoto (WKY) rat strain, as common in stress-associated functional GI disorders. Because changes in GI transit can alter microbiota composition, we investigated whether these are altered in WKY rats compared with the resilient Sprague-Dawley (SD) rats under basal conditions and characterized plasma lipid and metabolite differences. Bead transit was tracked by X-ray imaging to monitor gastric emptying (4 h), small intestine (SI) transit (9 h), and large intestine transit (12 h). Plasma extracts were analyzed by lipid and hydrophilic interaction liquid chromatography (HILIC) and liquid chromatography-mass spectrometry (LC-MS). Cecal microbial composition was determined by Illumina MiSeq 16S rRNA amplicon sequencing and analysis using the QIIME pipeline. Stomach retention of beads was 77% for WKY compared with 35% for SD rats. GI transit was decreased by 34% (9 h) and 21% (12 h) in WKY compared with SD rats. Excluding stomach retention, transiting beads moved 29% further along the SI over 4–9 h for WKY compared with SD rats. Cecal Ruminococcus, Roseburia, and unclassified Lachnospiraceae genera were less abundant in WKY rats, whereas the minor taxa Dorea, Turicibacter, and Lactobacillus were higher. Diglycerides, triglycerides, phosphatidyl-ethanolamines, and phosphatidylserine were lower in WKY rats, whereas cholesterol esters and taurocholic acids were higher. The unexpected WKY rat phenotype of delayed gastric emptying, yet rapid SI transit, was associated with altered lipid and metabolite profiles. The delayed gastric emptying of the WKY phenotype suggests this rat strain may be useful as a model for gastroparesis. NEW & NOTEWORTHY This study reveals that the stress-prone Wistar-Kyoto rat strain has a baseline physiology of gastroparesis and rapid small intestine transit, together with metabolic changes consistent with lipid metabolism-associated dysbiosis, compared with nonstress-prone rats. This suggests that the Wistar-Kyoto rat strain may be an appropriate animal model for gastroparesis. View this article's corresponding video summary at https://youtu.be/BeI39Jh2BLk .

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Neurons from neonatal hypertensive rats exhibit abnormal membrane properties in vitro

AJP Cell Physiology ◽

10.1152/ajpcell.1990.259.3.c389 ◽

1990 ◽

Vol 259 (3) ◽

pp. C389-C396 ◽

Cited By ~ 19

Author(s):

B. C. Jubelin ◽

M. S. Kannan

Keyword(s):

Action Potentials ◽

Membrane Properties ◽

Sprague Dawley ◽

Spontaneously Hypertensive ◽

Enzymatic Dissociation ◽

Sd Rats ◽

High Calcium ◽

Cervical Ganglia ◽

Wistar Kyoto

The in vitro membrane properties of neurons from superior cervical ganglia (SCG) of neonatal spontaneously hypertensive (SH), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats were studied with microelectrodes. Neurons were obtained by enzymatic dissociation, plated, irradiated, and studied after 2-5 wk. Most SH neurons showed multiple action potentials in response to an intracellular long-duration depolarizing pulse (multiple firing), whereas most neurons from WKY or SD rats generated only one or two action potentials. Multiple firing was inhibited by low concentrations of cobalt (10(-5) M) but not by tetrodotoxin (TTX) (3 x 10(-6) M). Neither high calcium (5-10 x 10(-3) M) nor the Ca2+(-)channel opener BAY K 8644 (10(-6) M) could induce multiple firing in SD or WKY neurons. However, multiple firing was readily induced by apamin (10(-6) M) or tetraethylammonium chloride (5 x 10(-3) M) (Ca2+(-)activated K+(-)channels blockers), with cobalt and TTX sensitivities similar to native multiple-firing neurons. We conclude that 1) multiple firing is characteristic of neonate SH rats SCG neurons in vitro and depends on regenerative Ca2+ currents; 2) multiple firing in SH neurons results from a lack of activation of a Ca2+(-)activated K+ conductance and not from a lack of internal Ca2+ availability; and 3) multiple firing in SCG neurons mirrors a default in K+ conductance common to all cells in genetically hypertensive individuals.

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Long-term captopril treatment restores natriuresis after carotid baroreceptor activation in the SHR

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.1.r70 ◽

1997 ◽

Vol 273 (1) ◽

pp. R70-R79

Author(s):

J. P. Valentin ◽

S. A. Mazbar ◽

M. H. Humphreys

Keyword(s):

Renal Plasma Flow ◽

Renal Nerves ◽

Sprague Dawley ◽

Wky Rats ◽

Sprague Dawley Rats ◽

Long Term Treatment ◽

Bilateral Carotid ◽

Wistar Kyoto ◽

Captopril Treatment

In anesthetized Sprague-Dawley rats, intermittent bilateral carotid artery traction (BilCAT) caused a transient decrease in mean arterial pressure (MAP) of 28 +/- 3 mmHg and led to a progressive increase in sodium excretion (UNaV) that nearly doubled 45-90 min after initiation of the repetitive application of BilCAT (P < 0.001). This natriuresis was accompanied by an increase in glomerular filtration rate (GFR) from 2.70 +/- 0.3 to 3.2 +/- 0.3 ml/min (P < 0.001), no change in renal plasma flow [clearance of p-aminohippurate (PAH)], and an increase in the fractional excretion of lithium. Rats with bilateral renal denervation exhibited neither natriuresis nor an increase in GFR in response to BilCAT despite similar vasodepression caused by the maneuver. Normotensive Wistar-Kyoto (WKY) rats responded to BilCAT like Sprague-Dawley rats, whereas spontaneously hypertensive rats (SHR) exhibited an exaggerated vasodepressor response to BilCAT (-51 +/- 3 mmHg) without increasing either UNaV or GFR. Separate groups of WKY and SHR were treated from 4 wk of age with captopril added to the drinking water at a concentration of 1 g/l. At 12-14 wk, both groups had lower MAP compared with untreated animals. Captopril treatment did not alter either the natriuretic response or the increase in GFR seen in untreated WKY after BilCAT, and the maneuver produced equivalent degrees of vasodepression as in controls. However, treated SHR now responded to BilCAT with increases in both UNaV and GFR that closely resembled the responses seen in Sprague-Dawley and WKY rats. These results suggest that BilCAT produces natriuresis through a pathway dependent on the renal nerves. This pathway does not function in untreated SHR despite similar vasodepression. Long-term treatment with captopril restores this reflex pathway in SHR, lending support to the concept that angiotensin II is critically linked to heightened sympathetic nerve activity and abnormal sodium metabolism in this strain.

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Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

Toxicologic Pathology ◽

10.1177/0192623320968716 ◽

2020 ◽

Vol 48 (8) ◽

pp. 994-1007

Author(s):

Timothy P. LaBranche ◽

Anna K. Kopec ◽

Srinivasa R. Mantena ◽

Brett D. Hollingshead ◽

Andrew W. Harrington ◽

...

Keyword(s):

Metabolic Syndrome ◽

Pharmaceutical Industry ◽

Liver Injury ◽

Hepatic Steatosis ◽

Sprague Dawley ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Sd Rats ◽

Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

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Lung injury in Fischer but not Sprague-Dawley rats after short-term hyperoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1990.259.6.l451 ◽

1990 ◽

Vol 259 (6) ◽

pp. L451-L458 ◽

Cited By ~ 5

Author(s):

L. S. He ◽

S. W. Chang ◽

P. Ortiz de Montellano ◽

T. J. Burke ◽

N. F. Voelkel

Keyword(s):

Lung Injury ◽

Lung Tissue ◽

Oxidant Stress ◽

Antioxidant Defenses ◽

Sprague Dawley ◽

Short Term ◽

Sd Rats ◽

Rat Lungs ◽

Rat Strain

The Fischer rat is known for its susceptibility to develop liver necrosis when challenged with paraquat (Smith et al., J. Pharmacol. Exp. Ther. 235: 172-177, 1985). We postulated that other organs, specifically the lung, may also be more susceptible to injury and examined whether lungs from Fischer (F) rats were injured more easily when challenged with active oxygen species than Sprague-Dawley (SD) rat lungs. We aimed to investigate whether increased susceptibility to oxidant injury was related to differences in lung antioxidant defenses. Perfused lungs from both rat strains were challenged by addition of H2O2 to the perfusate or by short-term hyperoxic ventilation. To assess nonoxidant modes of lung injury, we examined lung responses after exposure to protamine sulfate or neutrophil elastase. Intravascular H2O2 or 3 h in vitro hyperoxia caused lung edema in F but not SD rats, and elastase injured F rat lungs more than the lungs from SD rats. Protamine, however, injured the lungs from both strains to a similar degree. Catalase, but not superoxide dismutase or allopurinol, protected F rat lungs against edema, resulting from 3 h in vitro hyperoxia. The lung homogenate levels for reduced glutathione or conjugated dienes and the activities of lung tissue catalase, glutathione peroxidase, and cytochrome P-450 were not different between the two strains. Lung tissue ATP levels, however, were lower in F than in SD rats. Although the F rat strain appears to have an altered oxidant-antioxidant defense balance, the exact cause of the greater susceptibility to oxidant stress of the F rat strain remains elusive.

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