Y1- and α1-receptor control of basal hindlimb vascular tone

2004 ◽  
Vol 287 (1) ◽  
pp. R228-R233 ◽  
Author(s):  
Dwayne N. Jackson ◽  
Earl G. Noble ◽  
J. Kevin Shoemaker
Keyword(s):  
Vascular Tone ◽  
Receptor Activation ◽  
In Vivo Studies ◽  
Sprague Dawley ◽  
Vascular Conductance ◽  
Flow Profiles ◽  
Sprague Dawley Rats ◽  
Differential Flow

The role of endogenous Y1-receptor activation on skeletal muscle vasculature under baseline conditions is currently debated and no in vivo studies have been performed to address this issue. Therefore, this study was designed to address the effect of Y1-receptor and/or α1-adrenoceptor antagonism on basal hindlimb vascular conductance in male Sprague-Dawley rats in vivo. Left hindlimb vascular conductance, carotid artery mean arterial pressure, and heart rate were measured during low volume infusion of N2-(diphenylacetyl)- N-[(4-hydroxyphenyl)methyl]-d-arginine amide (BIBP3226; 100 μg/kg), prazosin (20 μg/kg), and combined blockade to the left hindlimb. Vascular conductance increased 1.5 ± 0.5 μl·min−1·mmHg−1 with BIBP3226 infusion, 1.7 ± 0.5 μl·min−1·mmHg−1 with prazosin infusion, and 4.8 ± 1.0 μl·min−1·mmHg−1 with combined blockade ( P < 0.05). Interestingly, systolic vascular conductance increased in all three conditions, but diastolic vascular conductance only increased in the two conditions where BIBP3226 was present. These data indicate that Y1-receptor activation plays an important role in the regulation of vascular conductance in the resting rat hindlimb. Furthermore, this effect was of the same magnitude as the α1-adrenoceptor contribution. The differential flow profiles following α1 blockade with and without Y1-receptor blockade supports local differences in receptor distribution.

scholarly journals Endothelin contributes to blunted renal autoregulation observed with a high-salt diet

2015 ◽  
Vol 309 (8) ◽  
pp. F687-F696 ◽  
Author(s):  
Robert C. Fellner ◽  
Zhengrong Guan ◽  
Anthony K. Cook ◽  
David M. Pollock ◽  
Edward W. Inscho
Keyword(s):  
Receptor Activation ◽  
High Salt ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Renal Autoregulation ◽  
Sprague Dawley Rats ◽  
Afferent Arterioles

Autoregulation of renal blood flow (RBF) is an essential function of the renal microcirculation that has been previously shown to be blunted by excessive dietary salt. Endogenous endothelin 1 (ET-1) is increased following a high-salt (HS) diet and contributes to the control of RBF but the differential effects of ET-1 on renal microvessel autoregulation in response to HS remain to be established. We hypothesized that a HS diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. Using highly selective antagonists, we observed that blockade of either ETA or ETB receptors was sufficient to restore normal autoregulatory behavior in afferent arterioles from HS-fed rats. Additionally, normal autoregulatory behavior was restored in vivo in HS-fed rats by simultaneous ETA and ETB receptor blockade, whereas blockade of ETB receptors alone showed significant improvement of normal autoregulation of RBF. Consistent with this observation, autoregulation of RBF in ETB receptor-deficient rats fed HS was similar to both ETB-deficient rats and transgenic control rats on normal-salt diets. These data support the hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, contributes to the blunted renal autoregulatory behavior in rats fed a HS diet.

scholarly journals Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

2018 ◽  
Vol 49 (4) ◽  
pp. 1420-1430 ◽  
Author(s):  
Lixiong He ◽  
Yujing Huang ◽  
Qiaonan Guo ◽  
Hui Zeng ◽  
Chuanfen Zheng ◽  
...  
Keyword(s):  
Low Dose ◽  
Soft Agar ◽  
Tumor Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
L02 Cells ◽  
Insight Into

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

scholarly journals Restoring ventilatory control using an adaptive bioelectronic system

2018 ◽  
Author(s):  
Ricardo Siu ◽  
James J Abbas ◽  
Brian K Hillen ◽  
Jefferson Gomes ◽  
Stefany Coxe ◽  
...  
Keyword(s):  
Closed Loop ◽  
In Vivo Studies ◽  
Sprague Dawley ◽  
Stimulation Parameters ◽  
Sprague Dawley Rats ◽  
Volume Profile ◽  
Stimulation Pattern ◽  
Stimulation Of

Ventilatory pacing via electrical stimulation of the phrenic nerve or of the diaphragm has been shown to enhance quality of life compared to mechanical ventilation. However, commercially-available ventilatory pacing devices require initial manual specification of stimulation parameters and frequent adjustment to achieve and maintain suitable ventilation over long periods of time. Here, we have developed an adaptive, closed-loop, neuromorphic, pattern-shaping controller capable of automatically determining a suitable stimulation pattern and adapting it to maintain a desired breath volume profile on a breath-by-breath basis. In vivo studies in anesthetized intact and C2-hemisected male Sprague-Dawley rats indicated that the controller was capable of automatically adapting stimulation parameters to attain a desired volume profile. Despite diaphragm hemiparesis, the controller was able to achieve a desired volume in the injured animals that did not differ from the tidal volume observed prior to injury (p=0.39). The closed-loop controller was developed and parametrized in a computational testbed prior to in-vivo assessment. This bioelectronic technology could serve as an individualized and autonomous respiratory pacing approach for support or recovery from ventilatory deficiency.

scholarly journals Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats

2018 ◽  
Vol 239 (1) ◽  
pp. 81-91 ◽  
Author(s):  
V Squicciarini ◽  
R Riquelme ◽  
K Wilsterman ◽  
G E Bentley ◽  
H E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Sprague Dawley ◽  
Ovarian Steroid ◽  
Sprague Dawley Rats ◽  
Mrna Expression Analysis

RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP-3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype.

scholarly journals Renal medullary ETB receptors produce diuresis and natriuresis via NOS1

2008 ◽  
Vol 294 (5) ◽  
pp. F1205-F1211 ◽  
Author(s):  
Daisuke Nakano ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Renal Medulla ◽  
Urinary Sodium Excretion ◽  
Receptor Activation ◽  
No Production ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Water Excretion ◽  
Sprague Dawley Rats

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ETB receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 μg·kg−1·h−1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats. Coinfusion of NG-propyl-l-arginine (10 μg·kg−1·h−1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 μg·kg−1·h−1) or RQIKIWFQNRRMKWKK-LRK5H-amide (18 μg·kg−1·h−1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ETB receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature

2003 ◽  
Vol 284 (6) ◽  
pp. H1942-H1948 ◽  
Author(s):  
M. Ursula Norman ◽  
Rebecca A. Lew ◽  
A. Ian Smith ◽  
Michael J. Hickey
Keyword(s):  
Specific Inhibitor ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Cerebral Microvasculature ◽  
Microvessel Permeability ◽  
The Brain ◽  
Cerebral Microvessel

Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) degrade bradykinin in vitro and are highly expressed in the brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70-kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor N-[1-( R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr- p-aminobenzoate (JA-2) resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by the inhibition of angiotensin-converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.

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

2006 ◽  
Vol 291 (2) ◽  
pp. F384-F394 ◽  
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.

Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B

2018 ◽  
Vol 38 (2) ◽  
pp. 193-200 ◽  
Author(s):  
Z-D Li ◽  
J Luo ◽  
L-H Jia ◽  
X-Y Wang ◽  
Z-K Xun ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Polymyxin B ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
C 30 ◽  
C 50

The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-β-D-glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood β2-microglobulin (β2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N-acetyl-β-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood β2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB.

scholarly journals Effects of Intestinal Microbiota on Pharmacokinetics of Crocin and Crocetin in Male Sprague-Dawley Rats

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 424
Author(s):  
Rajina Shakya ◽  
Mahesh R. Nepal ◽  
Mi Jeong Kang ◽  
Tae Cheon Jeong
Keyword(s):  
Intestinal Microbiota ◽  
Oral Treatment ◽  
Hepatic Metabolism ◽  
Crocus Sativus ◽  
Male Rats ◽  
Sprague Dawley ◽  
Gardenia Jasminoides ◽  
Sprague Dawley Rats

In addition to the hepatic metabolism, the role of intestinal microbiota in drug metabolism has been considered important in the biotransformation of xenobiotics. Crocin and its aglycone, crocetin, isolated from many plants, including the dried stigma of Crocus sativus and the fruit of Gardenia jasminoides, have been used in treatment of inflammation, cancer, and metabolic disorders. In this study, the effect of intestinal microbiota on the pharmacokinetics of crocin was studied following single oral treatment with 600 mg/kg crocin to male rats pre-treated with a mixture of antibiotics, such as cefadroxil, oxytetracycline, and erythromycin, for three consecutive days. Following crocin treatment, blood, urine, and feces were collected at various time points for evaluating pharmacokinetic characteristics of crocin and crocetin by using LC-MS. Results showed that intestinal absorption of crocin was relatively marginal when compared with that of crocetin, and that crocin metabolism to crocetin by intestinal microbiota would be a critical step for absorption. The present results clearly suggested that the in vivo pharmacological effects of crocin might be considered as the effects by its aglycone, crocetin, mainly, and that the metabolism of glycosidic natural products by intestinal microbiota should be considered to understand their pharmacodynamic actions.

Superoxide stimulates NaCl absorption by the thick ascending limb

2002 ◽  
Vol 283 (5) ◽  
pp. F957-F962 ◽  
Author(s):  
Pablo A. Ortiz ◽  
Jeffrey L. Garvin
Keyword(s):  
Xanthine Oxidase ◽  
In Vivo Studies ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Water Reabsorption ◽  
Cytotoxic Effects ◽  
Nacl Absorption ◽  
Enhanced Chemiluminescence ◽  
Sprague Dawley Rats

The thick ascending limb of the loop of Henle (THAL) plays an important role in the regulation of NaCl and water reabsorption. In vivo studies have shown that the free radical superoxide (O[Formula: see text]) stimulates Na and water reabsorption by the kidney. However, it is not known whether O[Formula: see text]regulates transport along the nephron in general or in the THAL specifically. We hypothesized that O[Formula: see text] stimulates THAL NaCl reabsorption. Cl absorption was measured in isolated, perfused THALs from Sprague-Dawley rats. First, we tested whether extracellular O[Formula: see text] stimulates Cl absorption. Addition of the O[Formula: see text]-generating system xanthine oxidase/hypoxanthine increased Cl absorption from 112.7 ± 12.0 to 146.2 ± 13.9 pmol · mm−1· min−1, a 33% increase ( P < 0.03). When superoxide dismutase (300 U/ml) was present in the bath, addition of xanthine oxidase/hypoxanthine did not significantly increase Cl absorption (116.9 ± 13.8 vs. 102.5 ± 8.5 pmol · mm−1· min−1). Furthermore, adding 200 nM H2O2to the bath did not significantly affect Cl absorption (from 130.3 ± 13.7 to 125.3 ± 19.6 pmol · mm−1· min−1). Because extracellular O[Formula: see text] stimulated Cl absorption, we next tested whether endogenously produced O[Formula: see text] could stimulate transport. Under basal conditions, THALs produced detectable amounts of O[Formula: see text], as measured by lucigenin-enhanced chemiluminescence. Adding the O[Formula: see text] scavenger tempol to the bath decreased Cl absorption from 198.1 ± 35.4 to 132.4 ± 23.5 pmol · mm−1· min−1, a 31% decrease ( P < 0.02). To make sure tempol was not exerting cytotoxic effects, we tested whether its effect was reversible. With tempol in the bath, Cl absorption was 117.2 ± 9.3 pmol · mm−1· min−1. Sixty minutes after tempol was removed from the bath, Cl absorption had increased to 149.2 ± 9.1 pmol · mm−1· min−1( P < 0.05). We concluded that both exogenous and endogenous O[Formula: see text] stimulate THAL NaCl absorption. To our knowledge, these are the first data showing a direct effect of O[Formula: see text] on nephron transport.

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