Nifedipine inhibits adrenal but not circulating catecholamine response to nicotinic stimulation in dogs

1994 ◽  
Vol 267 (6) ◽  
pp. R1545-R1551 ◽  
Author(s):  
R. Gaspo ◽  
N. Yamaguchi ◽  
J. de Champlain
Keyword(s):  
High Performance ◽  
Vehicle Control ◽  
Control Group ◽  
Vehicle Control Group ◽  
Aortic Blood ◽  
Catecholamine Response ◽  
Ca2 Channels ◽  
Sodium Plasma ◽  
Catecholamine Concentration

We investigated whether dihydropyridine-sensitive L-type Ca2+ channels are implicated in adrenal and sympathetic neural catecholamine release in response to nicotinic stimulation by 1,1-dimethyl-4-phenylpiperazinium (DMPP), a selective cholinergic nicotinic agonist, in dogs anesthetized with pentobarbital sodium. Plasma epinephrine and norepinephrine concentrations were measured in adrenal venous and aortic blood by a high-performance liquid chromatography-electrochemical method. In the vehicle control group, intravenous injection of DMPP (15 micrograms/kg iv) produced a significant increase in adrenal venous catecholamine output and aortic catecholamine concentration. These increasing responses were highly reproducible on the repetition of DMPP injection given 30 min after the first injection. In dogs receiving nifedipine (100 micrograms/kg iv), the net increase in adrenal venous epinephrine and norepinephrine output in response to DMPP was attenuated by 42% (P < 0.05), while no significant changes were observed in the aortic catecholamine response to DMPP. In dogs treated with pentolinium (1 mg/kg iv), both adrenal epinephrine and norepinephrine responses to DMPP were inhibited by 67% (P < 0.05) and 84% (P < 0.05), respectively. Furthermore, pentolinium inhibited aortic catecholamine response to DMPP by > 95% (P < 0.05). The present study suggests that DMPP-induced release of adrenal catecholamines was mediated, at least in part, through mechanisms involving dihydropyridine-sensitive L-type Ca2+ channels under in vivo conditions. By contrast, however, the results also suggest that dihydropyridine-sensitive L-type Ca2+ channels were not implicated in the neurotransmission at the level of sympathetic ganglions.

Implication of L-type Ca2+ channels in noncholinergic adrenal catecholamine secretion by endothelin-1 in vivo

1995 ◽  
Vol 269 (2) ◽  
pp. R287-R293 ◽  
Author(s):  
N. Yamaguchi
Keyword(s):  
High Performance ◽  
Cholinergic Receptor ◽  
Secondary Response ◽  
Control Group ◽  
Rapid Decline ◽  
Chromatography Method ◽  
Endothelin 1 ◽  
Liquid Chromatography Method ◽  
Ca2 Channels

The aim of the present study was to investigate if either dihydropyridine-sensitive L-type Ca2+ channels or cholinergic receptor-mediated mechanisms are implicated in endothelin-1 (ET)-induced adrenal catecholamine (CA) secretion in anesthetized dogs. ET was locally administered to the left adrenal gland via the left adrenolumbar artery. Plasma CA concentrations in adrenal venous and aortic blood were determined by a high-performance liquid chromatography method. In the control group, local infusion (1 min, 0.5 ml/min) of ET (the fixed total dose of 0.5 microgram given to the gland or approximately 0.0197 microgram/kg of body weight) resulted in a sharp increase in the basal CA output, followed by a rapid decline, and a relatively slow secondary response lasted over a period of 15-30 min. In the second group treated with nifedipine (5 micrograms or approximately 0.207 microgram/kg) similarly administered 10 min before ET infusion, the ET-induced first steep increase in CA output was significantly attenuated by approximately 75% (P < 0.05, n = 6). In dogs similarly receiving either pentolinium (1 mg or approximately 0.041 mg/kg) or atropine (0.5 mg or approximately 0.018 mg/kg), the ET-induced CA response remained unchanged. The results indicate that ET-induced adrenal CA release was largely mediated by the activation of dihydropyridine-sensitive L-type Ca2+ channels. Furthermore, neither nicotinic nor muscarinic receptors were functionally implicated in the CA response to ET. The study suggests the existence of noncholinergic mechanisms involved in the secretory action of ET on the adrenal medulla in the dog in vivo.

scholarly journals In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens

2021 ◽  
Author(s):  
Nicholas P. Clayton ◽  
Akash Jain ◽  
Stephanie A. Halasohoris ◽  
Lisa M. Pysz ◽  
Sanae Lembirik ◽  
...  
Keyword(s):  
Survival Rates ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Vehicle Control ◽  
Control Group ◽  
Post Challenge ◽  
Vehicle Control Group ◽  
Tebipenem Pivoxil

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 – 0.008 μg/ml for B. anthracis, ≤0.0005 – 0.03 μg/ml for Y. pestis, 0.25 – 1 μg/ml for B. mallei, and 1 – 4 μg/ml for B. pseudomallei. In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.

scholarly journals Assessment of the Toxicity and Carcinogenicity of Double-Walled Carbon Nanotubes in the Rat Lung After Intratracheal Instillation: A Two-Year Study

2021 ◽  
Author(s):  
David Bedell Alexander ◽  
Dina Mourad Saleh ◽  
Shengyong Luo ◽  
Omnia Hosny Mohamed Ahmed ◽  
William T. Alexander ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Lung Tumor ◽  
Industrial Applications ◽  
Vehicle Control ◽  
Control Group ◽  
Rat Lung ◽  
Vehicle Control Group ◽  
Double Walled Carbon Nanotubes ◽  
Walled Carbon Nanotubes

Abstract Background Considering the expanding industrial applications of carbon nanotubes (CNTs), safety assessment of these materials is far less than needed. Very few long-term in vivo studies have been carried out. This is the first 2-year in vivo study to assess the effects of double walled carbon nanotubes (DWCNTs) in the lung and pleura of rats after pulmonary exposure. Methods Rats were divided into six groups: Untreated, Vehicle, 3 DWCNT groups (0.12mg/rat, 0.25mg/rat and 0.5mg/rat), and MWCNT-7 (0.5mg/rat). The test materials were administrated by intratracheal - intrapulmonary spraying (TIPS) every other day for 15 days. Rats were observed without further treatment until sacrifice at weeks 52 and 104. Results DWCNT were biopersistent in the rat lung and induced marked pulmonary inflammation with a significant increase in macrophage count and levels of the chemotactic cytokines CCL2 and CCL3. In addition, the 0.5 mg DWCNT treated rats had significantly higher pulmonary collagen deposition compared to the vehicle controls. The development of carcinomas in the lungs of rats treated with 0.5 mg DWCNT (4/24) was not quite statistically higher (p = 0.0502) than the vehicle control group (0/25), however, the overall incidence of lung tumor development, bronchiolo-alveolar adenoma and bronchiolo-alveolar carcinoma combined, in the lungs of rats treated with 0.5 mg DWCNT (7/24) was statistically higher (p < 0.05) than the vehicle control group (1/25). Notably, two of the rats treated with DWCNT, one in the 0.25 mg group and one in the 0.5mg group, developed pleural mesotheliomas. However, both of these lesions developed in the visceral pleura, and unlike the rats administered MWCNT-7, rats administered DWCNT did not have elevated levels of HMGB1 in their pleural lavage fluids. Conclusions Our results demonstrate that DWCNTs are biopersistent in the rat lung and induce chronic inflammation. Moreover, rats treated with 0.5 mg DWCNT developed pleural fibrosis. While our results do not show that DWCNT is carcinogenic in the rat lung, total tumor incidence was significantly increased in the 0.5 mg DWCNT group. Taken together, these findings demonstrate that the possibility that at least some types of DWCNTs are fibrogenic and carcinogenic cannot be ignored.

Canine adrenal catecholamine response to VIP is blocked by PACAP-(6-27) in vivo

1997 ◽  
Vol 272 (5) ◽  
pp. R1606-R1612 ◽  
Author(s):  
R. Gaspo ◽  
L. Lamarche ◽  
J. de Champlain ◽  
N. Yamaguchi
Keyword(s):  
Muscarinic Receptors ◽  
Control Group ◽  
Plasma Catecholamine ◽  
Type I ◽  
Pituitary Adenylate Cyclase ◽  
Catecholamine Response ◽  
Anesthetized Dogs ◽  
Plasma Catecholamine Concentrations ◽  
Ca2 Channels

The goal of the present study was to characterize the adrenal catecholamine response to exogenous vasoactive intestinal peptide (VIP) in anesthetized dogs. We studied the potential involvement of mechanism(s) mediated by muscarinic receptors, L-type Ca2+ channels, VIP-ergic receptors, or pituitary adenylate cyclase-activating peptide (PACAP) receptors. The study consisted of five groups: a vehicle control group receiving VIP (5 micrograms) in the presence of saline and four drug-treated groups receiving VIP (5 micrograms) in the presence of either atropine (500 micrograms), nifedipine (50 micrograms), [Lys1,Pro2,5,Arg3,4,Tyr6]VIP (50 micrograms), or PACAP-(6-27) (50 micrograms). All drugs were locally infused to the left adrenal gland. Plasma catecholamine concentrations were measured in adrenal venous and aortic blood by a high-pressure liquid chromatography-electrochemical method. In the control group, VIP produced a significant increase in adrenal catecholamine output. Neither atropine, nifedipine, nor[Lys1,Pro2,5,Arg3,4,Tyr6]-VIP significantly affected the medullary response to VIP. In the presence of PACAP-(6-27), however, the catecholamine response to VIP was attenuated by approximately 77% (P < 0.05). The present study suggests that adrenal catecholamine secretion induced by exogenous VIP may be mediated by a PACAP-related mechanism, most probably through a PACAP type I receptor, in anesthetized dogs. The data also indicate that neither muscarinic receptors, VIP-ergic receptors, nor dihydropyridine-sensitive L-type Ca2+ channels are operative in the adrenal catecholamine response to exogenous VIP in vivo.

scholarly journals Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity.

1997 ◽  
Vol 41 (8) ◽  
pp. 1738-1742 ◽  
Author(s):  
D A Steinberg ◽  
M A Hurst ◽  
C A Fujii ◽  
A H Kung ◽  
J F Ho ◽  
...  
Keyword(s):  
Serial Passage ◽  
Vehicle Control ◽  
Control Group ◽  
Vehicle Control Group ◽  
Mueller Hinton ◽  
Immunocompetent Mice ◽  
Systemic Infections ◽  
Mueller Hinton Broth

Protegrin-1 (PG-1) is a cysteine-rich, 18-residue beta-sheet peptide isolated from porcine leukocytes with antimicrobial activity against a broad range of microorganisms. The MICs of PG-1 against representative gram-positive and gram-negative bacteria ranged from 0.12 to 2 microg/ml. At these levels, PG-1 was rapidly bactericidal in vitro, reducing the number of viable CFU of either methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa by more than three log units in less than 15 min. Resistance to PG-1 did not develop after 11 subculturings of P. aeruginosa or 18 subcultures of MRSA in Mueller-Hinton broth containing PG-1 at one-half the MIC. Under similar conditions of serial passage, the MICs of norfloxacin and gentamicin against P. aeruginosa increased 10 and 190 times, respectively. Similarly, the MIC of norfloxacin against MRSA increased 85 times. Immunocompetent mice inoculated intraperitoneally (i.p.) with P. aeruginosa or S. aureus exhibited 93 to 100% mortality in the vehicle control group compared with 0 to 27% mortality in animals that received a single i.p. injection of PG-1 (0.5 mg/kg of body weight). Mice inoculated with S. aureus by intravenous (i.v.) injection and dosed 0 to 60 min later with a single i.v. injection of PG-1 (5 mg/kg) had a mortality of 7 to 33%, compared to a mortality of 73 to 93% in the vehicle controls. In leukopenic mice inoculated i.v. with vancomycin-resistant Enterococcus faecium, mortality was 87% in the vehicle control group and 33% in animals that received a single i.v. injection of PG-1 (2.5 mg/kg). Taken together, these data indicate that PG-1 has potential for use as an antimicrobial agent in the treatment of local or systemic infections caused by clinically relevant pathogens.

A Teratological Evaluation and Postnatal Behavioral Screen of KF-868 In Rats

1985 ◽  
Vol 4 (1) ◽  
pp. 91-110 ◽  
Author(s):  
A. M. Hoberman ◽  
W. M. Weatherholtz ◽  
R. S. Durloo
Keyword(s):  
Body Weight ◽  
Vehicle Control ◽  
Female Rats ◽  
Reproductive Capacity ◽  
Control Group ◽  
Dosage Group ◽  
Vehicle Control Group ◽  
High Dosage Group ◽  
Significant Difference ◽  
Body Weights

The effects of a new experimental drug, KF-868, were investigated after administration to pregnant Sprague-Dawley rats at 0(vehicle), 0.1, 2.0, and 40.0 mg/kg per day during Days 7 through 17 of gestation by examination of term fetuses and naturally delivered offspring. Pregnant rats administered 0.1, 2.0, and 40.0 mg/kg per day gained significantly more weight during the dosage period than did the vehicle control group. Treatment-related physical signs, bloody crust on nose and stains on fur, were observed in the high dosage group. Fetal viability was significantly increased, and resorptions were significantly decreased for the mid and high dosage groups, when compared with the control group. Average fetal body weights for cesarean-delivered fetuses were less for the 40.0 mg/kg per day dosage groups than for the vehicle control group. Visceral and skeletal evaluations of fetuses revealed no difference between the control and test groups. Percent survival of pups was significantly less for the high dosage group than for the control group. Average rat body weights prior to mating for the high dosage group were generally less than for the control group. All physical and functional developmental values were comparable among the control and test groups. Evaluation of postweaning parameters of pups revealed no significant difference in sex maturation, behavior (open-field and water maze), and reproductive capacity. Average body weight gains during the 9-week growth period before mating were significantly less for the 40.0 mg/kg per day dosage group F1 generation female rats. Toxicity in fetuses and offspring was observed only at the highest dosage level. Dosage-dependent, significant increases in maternal body weight gain, as compared with control values, occurred for doses in the 3 KF-868-administered groups. These results indicate that 0.1 and 2.0 mg/kg per day dosages of KF-868 were not lethal and did not produce any adverse effects on the morphological or functional development of offspring. Toxicity was evident in offspring and fetuses of dams administered 40.0 mg/kg per day KF-868, 40,000 times as high as the daily therapeutic dose.

scholarly journals Direct effect of p,p'- DDT on mice liver

2016 ◽  
Vol 52 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Bárbara Arroyo-Salgado ◽  
Jesús Olivero-Verbel ◽  
Angélica Guerrero-Castilla
Keyword(s):  
Insulin Resistance ◽  
Epidemiological Data ◽  
Vehicle Control ◽  
Sesame Oil ◽  
Pcr Analysis ◽  
Control Group ◽  
Molecular Evidence ◽  
Vehicle Control Group ◽  
Mice Liver

ABSTRACT Contact with the pesticide dichlorodiphenyltrichloroethane (p,p′-DDT) can be the cause of various harmful effects in humans, wildlife, and the environment. This pesticide is known to be persistent, lipophilic, resistant to degradation, and bioaccumulive in the environment and to be slowly released into bloodstream. Growing evidence shows that exposure to DDT is linked to type 2 diabetes mellitus. Individuals exposed to elevated levels of DDT and its metabolite have an increased prevalence of diabetes and insulin resistance. To evaluate these possible relationships, experiments were performed on eight-week-old female mice, divided into three groups (n = 10 per group): Group 1 received a vehicle-control intraperitoneal (i.p.) injection of sesame oil; Groups 2 and 3 received an i.p. dose of 50 and 100 µg/g p,p′-DDT respectively, dissolved in sesame oil. All groups were treated once daily for four days. Real-time PCR analysis of several genes was undertaken. Additionally, biochemical parameters and histopathological changes were measured. NQO1, HMOX1, NR1I3 and NR3C1 were up-regulated in DDT-exposed animals compared to the vehicle control group, while only SREBP1 was down-regulated in the 100 µg/g group. MTTP and FABP5, not previously reported for DDT exposure, but involved in regulation of fatty acid fluxes, could also function as biomarkers cross-talking between these signaling pathways. These results suggest that beyond epidemiological data, there is increasing molecular evidence that DDT may mimic different processes involved in diabetes and insulin resistance pathways.

scholarly journals Quxie Capsule Inhibits Colon Tumor Growth Partially Through Foxo1-Mediated Apoptosis and Immune Modulation

2019 ◽  
Vol 18 ◽  
pp. 153473541984637 ◽  
Author(s):  
Dongmei Chen ◽  
Yufei Yang ◽  
Peiying Yang
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Immune Response ◽  
Treg Cells ◽  
Vehicle Control ◽  
Antitumor Efficacy ◽  
Th2 Cells ◽  
Control Group ◽  
Vehicle Control Group ◽  
Mouse Colon

Quxie capsule (QX), a herbal remedy used in traditional Chinese medicine, is routinely used in advanced colorectal cancer treatment in Xiyuan Hospital in Beijing, China. However, the mechanism(s) underlying the effect of QX in colorectal cancer remain unclear, which hampers the optimal use of QX for the treatment of the disease. The transcription factor forkhead box O1 (Foxo1) plays important roles in regulation of cell cycle, apoptosis, and immune response in various cancers. In this study, we examined the antitumor efficacy of QX in a mouse model of colorectal cancer and further investigated the mechanism by which QX regulated Foxo1 protein-mediated pathways. QX administered via gavage daily for 2 weeks in mice carrying CT26 mouse colon tumors resulted in significantly lower mean tumor weight (0.93 ± 0.32 g) compared with that in vehicle control-treated mice (1.57 ± 0.57 g, P <.05). Foxo1 protein expression in tumors was also higher in the QX group than that in the vehicle control group. Furthermore, QX treatment upregulated apoptotic proteins such as Fas, Bim, and cleaved caspase-3 in tumor tissue compared with those in the vehicle control group. Intriguingly, the ratios of Th1/Th2 and Th17/Treg cells and levels of T-bet protein (the key regulator of Th1 and Th2 cells) were higher while the level of Foxp3 (the key regulator of Treg cells) was lower in QX-treated mice compared to vehicle control mice, revealing that Foxo1 upregulated T-bet and downregulated Foxp3 and induced a shift in immune balance. This shift could be critical in the antitumor efficacy of QX. Furthermore, knocking down Foxo1 in human colon cancer HCT116 cells partially blocked the effect of QX-elicited antiproliferative activity. Together, these results suggest that QX exerts antitumor activity in CT26 mouse colon cancer model partially mediated by Foxo1-induced apoptosis and antitumor immune response.

Adrenergic receptors of adrenal medullary vasculature

1989 ◽  
Vol 256 (1) ◽  
pp. H233-H239
Author(s):  
D. A. Jordan ◽  
M. J. Breslow ◽  
K. L. Kubos ◽  
R. J. Traystman
Keyword(s):  
Nerve Stimulation ◽  
Adrenergic Receptors ◽  
High Performance ◽  
Vascular Tone ◽  
Splanchnic Nerve ◽  
Saline Control ◽  
Control Group ◽  
Medullary Blood Flow ◽  
Splanchnic Nerve Stimulation ◽  
Catecholamine Concentration

The present study evaluates possible effects of adrenal catecholamines, released by splanchnic nerve stimulation, on adrenal medullary blood flow (MQ) and adrenal catecholamine secretion (CS). Twelve pentobarbital-anesthetized mongrel dogs were subjected to three identical splanchnic nerve stimulations (5 V, 20 Hz, for 3 min) at 30-min intervals, and MQ (radiolabeled microsphere technique) and CS (high-performance liquid chromatography) were measured before and during each nerve stimulation. Animals were assigned to one of three groups and administered either saline, pindolol (1 and 4 mg/kg), or prazosin (1 and 4 mg/kg) before the second and third nerve stimulation, respectively. In the saline control group, each nerve stimulation resulted in similar increases in MQ and CS. Pindolol attenuated nerve stimulation-induced increases in MQ and CS by 50%, but had no effect on medullary catecholamine concentration. Prazosin augmented nerve stimulation-induced MQ, CS, and medullary catecholamine concentration by 35%. These data suggest that adrenal adrenergic receptors modulate elicited CS and mediate changes in adrenal medullary vascular tone.

scholarly journals α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093942
Author(s):  
Muhammad Younus ◽  
Muhammad Mohtasheem ul Hasan ◽  
Khalil Ahmad ◽  
Ali Sharif ◽  
Hafiz Muhammad Asif ◽  
...  
Keyword(s):  
High Performance ◽  
Wistar Rat ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Control Group ◽  
Control Drug ◽  
Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

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