Heme Induction with Delta-Aminolevulinic Acid Stimulates an Increase in Water and Electrolyte Excretion

Purpose. Studies were performed to examine hemodynamic and renal function before and after acute induction of the endogenous CO system with delta-aminolevulinic acid (DALA), which drives HO activity.Methods.In vivostudies were conducted on Inactin-anesthetized male Sprague Dawley rats (250–300 g) either with or without chronic pretreatment with L-NAME (50 mg/Kg, q12 hours x4d).Results. DALA (80 μmol/Kg, IV bolus) administration acutely increased endogenous CO production and HO-1 protein. In untreated and L-NAME-pretreated rats, DALA did not alter BP, GFR, or RBF but increased UF,UNaV, andUKV(untreated: Δ108.8 ± 0.28%, 172.1 ± 18.4%, and 165.2 ± 45.9%; pretreated: Δ109.4 ± 0.29%, 187.3 ± 26.9%, and 197.2 ± 45.7%). Acute administration of biliverdin (20 mg/kg, IV) and bilirubin (30 mg/kg, IV) to similarly treated animals did not alter UF,UNaV, andUKV.Conclusion. These results demonstrate that heme oxygenase induction increases urine and electrolyte excretion and suggest a direct tubular action of endogenous carbon monoxide.

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Carbon monoxide promotes endothelium-dependent constriction of isolated gracilis muscle arterioles

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00624.2002 ◽

2003 ◽

Vol 285 (3) ◽

pp. R536-R541 ◽

Cited By ~ 70

Author(s):

Fruzsina K. Johnson ◽

Robert A. Johnson

Keyword(s):

Carbon Monoxide ◽

Methyl Ester ◽

Aminolevulinic Acid ◽

No Synthase ◽

Gracilis Muscle ◽

Sprague Dawley ◽

No Donor ◽

First Order ◽

No Formation ◽

Sprague Dawley Rats

Vascular tissues express heme oxygenase, which metabolizes heme to form carbon monoxide (CO). CO promotes relaxation of vascular smooth muscle but also inhibits nitric oxide (NO) formation. This study examines the hypothesis that CO promotes endothelium- and NO synthase-dependent vasoconstriction of isolated arterioles. Studies were conducted on pressurized first-order gracilis muscle arterioles isolated from anesthetized male Sprague-Dawley rats. Exogenous CO, as well as a heme precursor, δ-aminolevulinic acid (δ-ALA), constricted arterioles with intact endothelium pretreated with phenylephrine; these effects were abolished by removal of the endothelium. CO- and δ-ALA-induced vasoconstrictions were converted to dilations by pretreatment with an inhibitor of NO synthase, Nω-nitro-l-arginine methyl ester, or with Nω-nitro-l-arginine methyl ester and an NO donor, sodium nitroprusside. Furthermore, CO-induced vasoconstriction was prevented by pretreatment with the NO synthase substrate l-arginine. This study shows that exogenous, as well as endogenously formed, CO can promote endothelium-dependent vasoconstriction in isolated gracilis muscle arterioles. Because CO-induced vasoconstriction is abolished by NO synthase blockade and by l-arginine, CO most likely promotes endothelium-dependent vasoconstriction by inhibiting endothelial NO formation.

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Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats

Journal of Psychopharmacology ◽

10.1177/0269881120944153 ◽

2020 ◽

Vol 34 (11) ◽

pp. 1316-1325

Author(s):

Ahmad A Altarifi ◽

Megan J Moerke ◽

Mohammad I Alsalem ◽

S Stevens Negus

Keyword(s):

Enzyme Inhibitor ◽

Abuse Potential ◽

Opioid Antagonist ◽

Repeated Treatment ◽

Acute Administration ◽

Sprague Dawley ◽

Drug Induced ◽

Sprague Dawley Rats ◽

Before And After ◽

Self Stimulation

Background: Tramadol is a widely used analgesic that activates mu-opioid receptors (MOR) and inhibits serotonin and norepinephrine transporters. This mixed pharmacology may limit both its own abuse potential and its modulation of abuse potential of other MOR agonists. Aims: This study used an intracranial self-stimulation (ICSS) procedure to compare abuse-related effects produced by acute or repeated treatment with tramadol or morphine in rats. Abuse potential in ICSS procedures is indicated by a drug-induced increase (or ‘facilitation’) of ICSS responding. Methods: Adult male Sprague–Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond on a lever for pulses of electrical brain stimulation. Tramadol effects were evaluated after acute administration (3.2–32 mg/kg) in the absence or presence of the opioid antagonist naltrexone, the CYP2D6 hepatic-enzyme inhibitor quinine or a combination of both. Additionally, both tramadol and morphine were also tested before and after repeated tramadol (32 mg/kg/day for six days) or repeated morphine (3.2 mg/kg/day for six days). Results: Acute tramadol produced primarily ICSS rate-decreasing effects that were antagonised by naltrexone but not by quinine or naltrexone + quinine. Tramadol also produced little or no ICSS facilitation after repeated tramadol or repeated morphine, and repeated tramadol did not enhance ICSS facilitation by morphine. By contrast, morphine-induced ICSS facilitation was enhanced by repeated morphine treatment. Conclusions: These results suggest that tramadol has lower abuse potential than other abused MOR agonists and that repeated tramadol exposure produces relatively little enhancement of abuse potential of other MOR agonists.

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Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF-β secretion: effect of the immunomodulator AS101 on this process

AJP Renal Physiology ◽

10.1152/ajprenal.00418.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. F384-F394 ◽

Cited By ~ 24

Author(s):

Inna Sinuani ◽

Zhan Averbukh ◽

Inna Gitelman ◽

Micha J. Rapoport ◽

Judit Sandbank ◽

...

Keyword(s):

Mesangial Cells ◽

Renal Tissue ◽

Sprague Dawley ◽

Compensatory Renal Growth ◽

Sprague Dawley Rats ◽

Before And After ◽

Renal Tubular ◽

Immunohistochemical Studies

The present study investigated the role of IL-10 produced by the mesangial cells in postnephrectomy compensatory renal growth and the effect of the immunomodulator AS101 on this process. One hundred forty unilateral nephrectomized and sham-operated male Sprague-Dawley rats were treated by AS101 or PBS before and after surgery. The results show that secretion of IL-10 and TGF-β by mesangial cells isolated from the remaining kidneys was increased significantly, compared with those of control and sham animals. Moreover, TGF-β secretion by mesangial cells was increased after the addition of exogenous recombinant IL-10 and inhibited in the presence of neutralizing anti-IL-10 antibodies. In vivo, compensatory growth of the remaining kidneys was associated with significant increase in IL-10 content in renal tissues and plasma. Immunohistochemical studies show that IL-10 was produced by mesangial cells. Elevated IL-10 levels were followed by the rise in TGF-β content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF-β expression in plasma and kidney tissues and results in 25% reduction in the fresh and fractional kidney weight and decreased hypertrophy of tubular cells (protein/DNA ratio, morphometric analysis). Taken together, these data demonstrate that TGF-β production by mesangial cells is IL-10 dependent. Mesangial cells are the major source of IL-10 in kidneys. AS101, by inhibiting the activity of IL-10, decreases TGF-β production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.

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Acute hypoxia upregulates NOS gene expression in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.3.r905 ◽

1997 ◽

Vol 273 (3) ◽

pp. R905-R910 ◽

Cited By ~ 20

Author(s):

B. Gess ◽

K. Schricker ◽

M. Pfeifer ◽

A. Kurtz

Keyword(s):

Gene Expression ◽

Carbon Monoxide ◽

Acute Hypoxia ◽

Mrna Levels ◽

General Effect ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Flow Through ◽

Ribonuclease Protection

This study aimed to investigate the influence of acute tissue hypoxygenation on the expression of NO synthase (NOS) genes in vivo. To this end, male Sprague-Dawley rats were exposed either to 9% oxygen or to 0.1% carbon monoxide for 6 h, and mRNA levels of NOS-I, -II, and -III in kidneys, livers, lungs, and left and right heart ventricles were assayed by ribonuclease protection. For comparison, mRNA levels of erythropoietin were also measured in these tissues. NOS-III mRNA was highly abundant in all organs investigated. NOS-II mRNA was detected in lungs and hearts but not in kidneys and livers. NOS-I mRNA was found in kidneys, lungs, and hearts but not in livers. NOS-III mRNA levels were upregulated by hypoxia in all tissues examined, with the least effect (1.2-fold) in the left ventricle and the greatest effect (2.6-fold) in the lung. NOS-II mRNA was substantially downregulated in the ventricles by both treatments but not changed in the lung. NOS-I mRNA was upregulated by carbon monoxide in kidneys and lungs and by 9% oxygen in the lung. These findings suggest that NOS-III and possibly also NOS-I gene expression behave like oxygen-regulated genes, whereas the general effect of tissue hypoxygenation on NOS-II gene expression is less clear. Because NOS-III is primarily expressed in endothelial cells, a general upregulation of NOS in these cells may be of relevance for the regulation and maintenance of blood flow through hypoxic tissues.

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Toxicokinetic and Genotoxicity Study of NNK in Male Sprague-Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage

Toxicological Sciences ◽

10.1093/toxsci/kfab049 ◽

2021 ◽

Author(s):

Shu-Chieh Hu ◽

Matthew S Bryant ◽

Estatira Sepehr ◽

Hyun-Ki Kang ◽

Raul Trbojevich ◽

...

Keyword(s):

Human Lung ◽

Inhalation Exposure ◽

Systemic Exposure ◽

Sprague Dawley ◽

Oral Gavage ◽

Sd Rats ◽

New Information ◽

Sprague Dawley Rats ◽

Tissue Specimens

Abstract The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5x10−5, 5x10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 hour. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal (IP) injection and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated timepoints and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 hours post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the toxicokinetics and genotoxicity of NNK.

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Pharmacological comparison of four biopolymeric natural gums as hemostatic agents for management of bleeding wounds: preliminary in vitro and in vivo results

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00237-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Himanshu Kushwah ◽

Nidhi Sandal ◽

Meenakshi Chauhan ◽

Gaurav Mittal

Keyword(s):

Xanthan Gum ◽

Guar Gum ◽

Human Lymphocytes ◽

Sprague Dawley ◽

Gum Tragacanth ◽

Civilian Trauma ◽

Sprague Dawley Rats ◽

Cytotoxicity Studies

Abstract Background Uncontrolled bleeding is one of the primary reasons for preventable death in both civilian trauma and military battle field. This study evaluates in vitro and in vivo hemostatic potential of four biopolymeric natural gums, namely, gum tragacanth, guar gum, xanthan gum, and gum acacia. In vitro evaluation of whole blood clotting time and erythrocyte agglutination assay were carried out. In vitro cytotoxicity studies with respect to each gum were done in human lymphocytes to ascertain percent cell viability. In vivo hemostatic potential of each gum (as sponge dressing and powder form) was evaluated in Sprague Dawley rats using tail bleeding assay and compared with commercially available hemostatic sponge. Other important parameters like (a) time taken for complete hemostasis, (b) amount of blood absorbed, (c) adherence strength of developed hemostatic dressing(s), (d) incidence of re-bleeding, and (e) survival of animals were also studied. Results Of the four test gums studied, xanthan gum (@3mg/ml of blood) and gum tragacanth (@35mg/ml of blood) were able to clot blood in least time (58.75±6.408 s and 59.00±2.082 s, respectively) and exhibited very good hemostatic potential in vitro. Except for xanthan gum, all other test gums did not exhibit any significant cytotoxicity at different time points till 24 h. In rat tail bleeding experiments, gum tragacanth sponge dressing and powder achieved hemostasis in least time (156.2±12.86 s and 76±12.55 s, respectively) and much earlier than commercially available product (333.3±38.84 s; p˂0.01). Conclusion Results indicate potential of gum tragacanth to be developed into a suitable hemostatic product.

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Bioavailability in Vivo of Benzo[a]Pyrene Adsorbed to Diesel Particulate

Toxicology and Industrial Health ◽

10.1177/074823379100700302 ◽

1991 ◽

Vol 7 (3) ◽

pp. 125-139 ◽

Cited By ~ 6

Author(s):

David R. Bevan ◽

David M. Ruggio

Keyword(s):

Health Risks ◽

Quantitative Description ◽

Intratracheal Instillation ◽

Direct Analysis ◽

Sprague Dawley ◽

Reasonable Estimate ◽

Diesel Particulate ◽

Sprague Dawley Rats

To evaluate health risks associated with exposure to particulates in the environment, it is necessary to quantify the bioavailability of carcinogens associated with the particulates. Direct analysis of bioavailability in vivo is most readily accomplished by adsorbing a radiolabeled form of the carcinogen to the particulate. A sam ple of native diesel particulate collected from an Oldsmobile die sel engine that contained 1.03 μ g benzo[ a] pyrene ( BaP)/ g particulate was supplemented with exogenous [ 3 H]- BaP to pro duce a particulate containing 2.62 μ g BaP/g. To insure that elu tion of BaP from native and [3 H] -BaP-supplemented particulate was similar, in vitro analyses were performed. When using phos pholipid vesicles composed of dimyristoylphosphatidylcholine (DMPC), 1.52% of total BaP was eluted from native particulate into the vesicles in 18 hrs; from [ 3 H] -BaP supplemented particu late, 1.68% was eluted. Using toluene as eluent, 2.55% was eluted from native particulate, and 8.25% from supplemented particulate, in 6 hrs. Supplemented particulate was then instilled intratracheally into male Sprague-Dawley rats and distribution of radioactivity was analyzed at selected times over 3 days. About 50% of radioactivity remained in lungs at 3 days following instil lation, with 30% being excreted into feces and the remainder dis tributed throughout the organs of the rats. To estimate the amount of radioactivity that entered feces through swallowing of a portion of the instilled dose, [3 H] -BaP-supplemented particu late was instilled intratracheally into rats that had a cannula sur gically implanted in the bile duct. Rate of elimination of radio activity into bile was monitored; 10.6% of radioactivity was re covered in 6 hr, an amount slightly lower than the 12.8% ex creted in 6 hrs into feces of animals with intact bile ducts. Our studies provide a quantitative description of the distribution of BaP and its metabolites following intratracheal instillation of diesel particulate. Because rates of elution of BaP in vitro are similar for native diesel particulate and particulate with supple mental [ 3H] -BaP, our results provide a reasonable estimate of the bioavailability in vivo of BaP associated with diesel particu late.

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Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00015.2016 ◽

2016 ◽

Vol 120 (10) ◽

pp. 1186-1195 ◽

Cited By ~ 9

Author(s):

Barbara J. Morgan ◽

Russell Adrian ◽

Zun-yi Wang ◽

Melissa L. Bates ◽

John M. Dopp

Keyword(s):

Intermittent Hypoxia ◽

Acute Hypoxia ◽

Sprague Dawley ◽

Glomus Cell ◽

Stimulus Response ◽

Sprague Dawley Rats ◽

Ventilatory Equivalent ◽

Before And After ◽

Conscious Animals ◽

Carotid Body Glomus Cells

We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for V̇co2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the V̇e/V̇co2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation.

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Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats

Cells ◽

10.3390/cells10040856 ◽

2021 ◽

Vol 10 (4) ◽

pp. 856

Author(s):

Eun Young Kim ◽

Stuart E. Dryer

Keyword(s):

Renal Function ◽

Protective Effect ◽

Renal Fibrosis ◽

Transient Receptor Potential ◽

Smooth Muscle Actin ◽

Receptor Potential ◽

Sprague Dawley ◽

Age Related ◽

Sprague Dawley Rats ◽

Transient Receptor

Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal function owing to effects on almost every renal compartment in humans and rodents. Here, we have examined the role of TRPC6 in driving inflammation and fibrosis during aging in Sprague-Dawley rats. This was assessed in rats with non-functional TRPC6 channels owing to CRISPR-Cas9 deletion of a portion of the ankyrin repeat domain required for the assembly of functional TRPC6 channels (Trpc6del/del rats). Wild-type littermates (Trpc6wt/wt rats) were used as controls. Animals were evaluated at 2 months and 12 months of age. There was no sign of kidney disease at 2 months of age, regardless of genotype. However, by 12 months of age, all rats examined showed declines in renal function associated with albuminuria, azotemia and increased urine excretion of β2–microglobulin, a marker for proximal tubule pathology. These changes were equally severe in Trpc6wt/wt and Trpc6del/del rats. We also observed age-related increases in renal cortical expression of markers of fibrosis (α-smooth muscle actin and vimentin) and inflammation (NLRP3 and pro-IL−1β), and there was no detectable protective effect of TRPC6 inactivation. Tubulointerstitial fibrosis assessed from histology also appeared equally severe in Trpc6wt/wt and Trpc6del/del rats. By contrast, glomerular pathology, blindly scored from histological sections, suggested a significant protective effect of TRPC6 inactivation, but only within the glomerular compartment.

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