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At least 973 records · Page 54Linked to original sources
PubMed1996

Predator-elicited flight responses in Swiss-Webster mice: an experimental model of panic attacks.

1. The nosological status of panic disorder is still a matter of debate. Nevertheless, evidence is emerging that panic attacks have a different pattern of drug responsiveness from other forms of anxiety. 2. Several experimental animal models of panic attacks have been developed. These vary in the extent to which they meet criteria for face validity, predictive validity and construct validity, normally applied to such models. 3. In the present review, the authors examine the possibility that predator-elicited flight responses in Swiss-Webster mice might serve as an experimental model for the screening of panic-modulating drugs. 4. Drug effects on flight responses clearly indicate that this model has good predictive validity as panic-promoting agents increase flight reactions, while panicolytic drug challenge induces opposite effects. In addition, drugs devoid of any effect on panic attack, also do not alter flight behavior. 5. These findings strongly suggest that the model of predator-elicited flight responses in Swiss-Webster mice is useful for the investigation of panic-modulating drugs.

Animals↗
PubMed2001

Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo.

We investigated the effects of YM905 [(+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate], a new orally active muscarinic M3-receptor antagonist, on bowel dysfunction in vivo using experimental models that reproduce the symptoms present in irritable bowel syndrome (IBS). YM905 potently inhibited restraint stress-induced fecal pellet output in fed rats (ED50: 4.0 mg/kg) and diarrhea in fasted rats (ED50: 1.7 mg/kg), with similar potencies to the inhibition of bethanechol-, neostigmine- and nicotine-induced fecal pellet output in rats (ED50: 3.3, 7.9 and 4.5 mg/kg, respectively). YM905 also inhibited 5-hydroxytryptamine (5-HT)-, prostaglandin E2- and castor oil-induced secretory diarrhea in mice (ED50: 5.5, 14 and 6.3 mg/kg, respectively), but showed no significant effect on cholera toxin-induced intestinal secretion in mice. In addition, YM905 (3, 10 mg/kg) reversed morphine-decreased postprandial defecation in ferrets, a model of spastic constipation, whereas remosetron, a 5-HT3-receptor antagonist, was not effective. The mode of YM905 action was similar to that of darifenacin, a selective M3-receptor antagonist, with equivalent potencies. By contrast, propantheline, an antimuscarinic drug that has been used for IBS, was much less potent. These results show that YM905 ameliorates a wide spectrum of bowel dysfunctions through the blockade of M3 receptors, suggesting its therapeutic potential for treating IBS.

Animals↗
PubMed1977

[Spontaneously occuring and experimentally induced enzymatic changes in the rat parotid gland: a possible experimental model of ageing (author's transl)].

The activity, specificity and stability of many enzymes decreases in ageing organisms. This fact is attributed to the accumulation of errors in protein biosynthesis. Due to its very active protein metabolism, the parotid gland is a suitable experimental model for the investigation of such age-dependent processes. By administration of 5-bromodeoxyuridine to young rats, changes of isoamylase.activity were induced in the parotid glands which were strikingly similar to those found earlier in control normally-aged animals.

Aging↗
PubMed2004

Indolalkylamines derivatives as antioxidant and neuroprotective agents in an experimental model of Parkinson's disease.

BACKGROUND: The neuroprotective effect of N-(2-propynyl)2-(5-benzyloxy-indol)methylamine (PF 9601N), a novel MAO B inhibitor, and its metabolite FA 72 on the human neuroblastoma SHSY5Y cell line lesioned with (300 microM) dopamine was assessed and compared with that of 1-deprenyl assayed at identical experimental conditions. MATERIAL/METHODS: Using this experimental model, PF 961N showed a neuroprotective effect in a dose-dependent manner, and at a concentration of 10 pM a 20% recovery of cell viability was observed. However, the metabolite FA72 assayed under the same experimental conditions showed an increase in cell viability of nearly 50%. In the case of l-deprenyl, a concentration of 100 microM was necessary to recover only 10% of cell viability. RESULTS: This neuroprotective effect could be explained in terms of the antioxidant capacity of PF 9601N. In this context, the antioxidant capacities of the novel series of MAO inhibitors, PF 9601N and its analogues, were evaluated by their inhibition of the auto-oxidation of dopamine to melanin and by the dichlorofluorescein and 2-deoxyribose methods. CONCLUSIONS: All of these compounds have the basic structure of an indole ring in common, but show different substituents at different positions in it. The corresponding structure-activity relationship studies allowed us to conclude that the presence of a benzyloxy group, or a hydroxy or methoxy group, at position 5 of the indol ring enhanced these antioxidant characteristics, presenting a decreasing order of antioxidant activity of the primary > secondary > tertiary amines. The antioxidant properties of PF 9601 N would explain its neuroprotective effect observed in SHSY5Y cells lesioned with dopamine.

Animals↗
PubMed2005

rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep.

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.

Animals↗
PubMed2002

Biomechanical analyses of whiplash injuries using an experimental model.

Neck pain and headaches are the two most common symptoms of whiplash. The working hypothesis is that pain originates from excessive motions in the upper and lower cervical segments. The research design used an intact human cadaver head-neck complex as an experimental model. The intact head-neck preparation was fixed at the thoracic end with the head unconstrained. Retroreflective targets were placed on the mastoid process, anterior regions of the vertebral bodies, and lateral masses at every spinal level. Whiplash loading was delivered using a mini-sled pendulum device. A six-axis load cell and an accelerometer were attached to the inferior fixation of the specimen. High-speed video cameras were used to obtain the kinematics. During the initial stages of loading, a transient decoupling of the head occurs with respect to the neck exhibiting a lag of the cranium. The upper cervical spine-head undergoes local flexion concomitant with a lag of the head while the lower column is in local extension. This establishes a reverse curvature to the head-neck complex. With continuing application of whiplash loading, the inertia of the head catches up with the neck. Later, the entire head-neck complex is under an extension mode with a single extension curvature. The lower cervical facet joint kinematics demonstrates varying local compression and sliding. While the anterior- and posterior-most regions of the facet joint slide, the posterior-most region of the joint compresses more than the anterior-most region. These varying kinematics at the two ends of the facet joint result in a pinching mechanism. Excessive flexion of the posterior upper cervical regions can be correlated to headaches. The pinching mechanism of the facet joints can be correlated to neck pain. The kinematics of the soft tissue-related structures explain the mechanism of these common whiplash associated disorders.

Aged↗
PubMed1995

Atherogenic effects of cyclosporine in an experimental model of arterial autograft.

One of the effects attributed to CsA is a possible acceleration of atherogenic processes, which contributes to the failure of transplanted organs. This study was undertaken to evaluate the effect of CsA and two vehicles, cremophor and ethanol, in an experimental model of arterial autograft in the rat. Female Sprague-Dawley rats were distributed into 3 study groups: Group 1 (control) had an arterial autograft in the common iliac artery without pretreatment; group 2 (CsA-cremophor) animals were pretreated with a daily dose of CsA (5 mg/kg, Sandimmun) for 4 days before the autograft was made; and group 3 (CsA-ethanol + Tween) animals were pretreated for 4 days before implantation of the autograft with CsA in a vehicle of ethanol + Tween at the same dose as used in group 2 (5 mg/kg). The study periods were 7, 14, 21, 30, and 50 postoperative days. Studies were made by optical microscopy, transmission electron microscopy, scanning electron microscopy, and autoradiography. Evaluation of the results showed that in the control group the postoperative repair process lead to formation of an intimal neolayer throughout the entire surgical zone, with scant participation of white cells. Group 2 (CsA-cremophor) had a marked increase in luminal thrombogenicity, important adhesion and infiltration of white cells, loss of smooth muscle cells in the medial layer, and atherogenic degeneration of the medial layer. The generation of the neointimal layer is delayed by 2 weeks with respect to the control group. However, once the neointimal begins to form, its thickness increases rapidly, reaching values similar to those seen in the control group at 50 days. The myointima also shows atherogenic characteristics, such as monocyte-macrophage infiltration and dystrophic calcification. In group 3 (CsA-ethanol+Tween, that is, CsA in a nonoleaginous vehicle), the effects were similar to those seen in group 2 (CsA-cremophor), with a reduction in the presence of lipid-laden cells in the medial layer. Based on these observations, we conclude that CsA per se induced atherogenic changes in the repair process of the arterial lesion that were independent of the vehicle of administration. CsA delayed, but did not inhibit, formation of a myointima and the myointima formed exhibited atherogenic characteristics. The most important effects were noted in the medial layer, which experienced intense degeneration.

Animals↗
PubMed2002

Changes in tissue-oxidative stress markers in an experimental model of laparoscopic donor nephrectomy.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) is associated with prolonged warm ischemia, which could potentially increase oxidative stress in the graft. Because pneumoperitoneum (Pp) used to facilitate LDN impairs renal perfusion, it could augment the effects of warm ischemia. Our experimental, randomized, controlled study with blind outcome assessment is the first to address this possibility. METHODS: Wistar-Albino rats were randomized to 4 groups. Controls were subjected to a sham operation; the remainder were subjected to Pp with or without warm ischemia of differing durations. The kidneys were removed at the end of each experiment. The concentrations of malondialdehyde (MDA), protein carbonyl, and sulfhydryl groups and the activities of superoxide dismutase (SOD) and catalase were measured in renal samples as markers of oxidative stress. Renal samples were also evaluated histopathologically using light microscopy. RESULTS: Pp promoted oxidative stress in renal tissues, with an increase of MDA and protein carbonyls and a decrease in protein sulfhydryls and SOD activity. Warm ischemia exerted an additive effect on Pp-associated oxidative stress only when sustained for 10 minutes. These changes occurred in the absence of light-microscopic evidence of overt tissue damage. CONCLUSION: In an experimental model resembling LDN, Pp and 10 minutes of warm ischemia emerged as additive factors with respect to causing increased oxidative stress in the kidney. Because these effects imply subtle injury not only in the harvested kidneys of live donors but also in the kidneys the donors retain, avoiding Pp and warm ischemia above 5 minutes during LDN appears advisable.

Animals↗
PubMedDate not supplied

Cytochromes P450 and experimental models of drug metabolism.

For the development of new drugs, evaluation of drug-drug interactions with already known compounds, as well as for better understanding of metabolism pathways of various toxicants and pollutants, we studied the drug metabolism mediated by cytochromes P450. The experimental approach is based on animal drug-metabolising systems. From the ethical as well as rational reasons, the selection of an appropriate system is crucial. Here, it is necessary to decide on the basis of expected CYP system involved. For CYP1A-mediated pathways, all the commonly used experimental models are appropriate except probably the dog. On the contrary, the dog seems to be suitable for modelling of processes depending on the CYP2D. With CYP2C, which is possibly the most large and complicated subfamily, the systems based on monkey (Maccacus rhesus) may be a good representative. The CYP3A seems to be well modelled by pig or minipig CYP3A29. Detailed studies on activities with individual isolated CYP forms are needed to understand in full all aspects of inter-species differences and variations.

Animals↗
PubMed1986

Squamous metaplasia in the trachea: the tracheotomized rabbit as an experimental model and implications in recurrent papillomatosis.

Squamous metaplasia following tracheotomy has been well documented. Most studies have dealt primarily with changes at--or adjacent to--the cuff site and have failed to evaluate its effect in the distal trachea. We have used rabbits as experimental models for the induction of tracheal squamous metaplasia, using uncuffed tracheotomy tubes. Rabbits were routinely killed 24, 36, 48, 72, 120, and 168 hours posttracheotomy, and the entire larynx, trachea, and main-stem bronchi were step-sectioned for histologic examination. Patchy areas of squamous metaplasia were found in all rabbits with tracheotomy equal to or longer than 48 hours. The metaplasia appeared to increase with time of intubation. Induction of squamous metaplasia (following tracheotomy as a contributing factor to the spread of laryngeal papillomatosis) is discussed.

Animals↗
PubMed1992

Experimental models of immunization against schistosomes: lessons for vaccine development.

Schistosomiasis is a debilitating, and sometimes deadly, parasitic infection that afflicts hundreds of millions of people living in developing countries. One of the best hopes for control of this disease is vaccine development. Studies on experimental models of attenuated vaccines have proven that high levels of protective immunity can be achieved. In these systems, resistance has been shown to be directed against the migrating larval stages of the parasite and to have both cellular and humoral components. Several candidate vaccine immunogens have been identified on the basis of antibody reactivity. However, the level of protection induced by immunization with nonliving vaccines has at yet not approached the level observed with attenuated infection. Current challenges to vaccine development include identification of protective T cell immunogens, determination of ways to strengthen the immunogenicity of isolated parasite antigens, and development of methodologies to selectively stimulate protective, as opposed to ineffective or even detrimental, immune responses.

Animals↗
PubMedDate not supplied

Myocardial dysfunction in an experimental model of autoimmune myocarditis: role of IFN-gamma.

Experimental autoimmune myocarditis obtained in mice by immunization with heart antigens is characterized by the presence of lymphomononuclear infiltrates in atria and ventricles. Here we show the ability of soluble factors released by immune cells from mice immunized with heart antigens to decrease heart contractility in a similar way to a muscarinic agonist. These effects appear to be mediated by IFN-gamma since all of them could be blocked by an anti-IFN-gamma monoclonal antibody. Moreover, the negative inotropic effect induced by immune cell-conditioned media was blocked by atropine, confirming previous findings that IFN acts as a muscarinic agonist on isolated atria. The role of locally released cytokines and especially of IFN-gamma was also evaluated in infiltrated autoimmune myocarditis hearts; thus, the addition of monoclonal anti-IFN-gamma antibody reversed the decreased contractility characteristics of this model. We conclude that IFN released both systemically and locally by autoreactive T cells may contribute to the impaired cardiac function in this experimental model of autoimmune myocarditis.

Animals↗
PubMed1998

The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit.

It is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1-20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1-10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP's effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.

Animals↗
PubMed1996

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential.

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 micrograms.kg-1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean +/- S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 +/- 0.3 mumol.kg-1 and the highest dose (1000 micrograms.kg-1) produced a 67 +/- 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1- piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1 , 1-biphenyl]-4-carboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 mumol.kg-1, i.v.). Compared to sumatriptan (pD2: 6.12 +/- 0.15; Emax: 31.3 +/- 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 +/- 0.2; Emax: 21.0 +/- 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects.

Animals↗
PubMed2003

Levels of TGFbeta1 in gingival crevicular fluid during a 21-day experimental model of gingivitis.

OBJECTIVE: TGFbeta1 is a multifunctional growth factor with both pro- and anti-inflammatory properties. This study aimed to determine levels of TGFbeta1 in gingival crevicular fluid (GCF), serum and plasma in the early stages of gingival inflammation. DESIGN: A 21-day experimental model of gingivitis employing a split mouth design with a soft vinyl splint used to cover test teeth during brushing. SUBJECTS: Ten healthy volunteers (mean age 21 years; five males and five females). METHODS: GCF and blood (with and without EDTA) was collected on days 0, 7, 14 and 21. GCF volumes were measured on a precalibrated Periotron 8000TM. Clinical indices of gingival inflammation and plaque levels were obtained after GCF sampling. Normal brushing resumed after GCF collection on day 21 and final samples were collected on day 35. TGFbeta1 and alkaline phosphatase (ALP) levels were determined using enhanced chemiluminescent methods. RESULTS: Clinical indices and GCF volumes increased at test sites during the 21-day test period. Concentrations of TGFbeta1 and ALP in GCF (test and control), serum and plasma did not change throughout the study (P > 0.3). However, total amounts of TGFbeta1 (pg sample-1) and ALP (mu IU sample-1) in GCF increased at test sites and were significantly higher than baseline values at days 7, 14 and 21 (P < 0.04). Control sites showed no variation in TGFbeta1 or ALP levels throughout the study period (P > 0.35). All parameters at test sites returned to control levels at day 35 (P > 0.3). CONCLUSION: The data indicate that GCF TGFbeta1 levels increase early in plaque-induced inflammation. Whether the biological consequence of this site-specific increase is pro- or anti-inflammatory in nature remains to be elucidated.

Adult↗
PubMed1989

Effects of nicergoline in experimental models related to pathogenesis of migraine.

The effect of nicergoline on cerebral blood flow (CBF), cerebrovascular resistance, the constriction of cerebral vessels caused reflectorily or by 5-hydroxytryptamine (5-HT) and on the transport of 5-HT in rat brain synaptosomes was studied using different experimental models. Nicergoline reduced cerebrovascular resistance in the carotid and vertebrobasilar system. The drug decreased carotid blood flow and local cortical CBF, preceded in some experiments by short-lasting CBF increase. Nicergoline almost completely inhibited brain vessels responses in the carotid and vertebrobasilar systems after tibial nerve stimulation. Simultaneously, inhibition of reflectory discharges of the sympathetic nerves was observed. Nicergoline showed an antiserotonin action by antagonizing the 5-HT effect on the cerebral circulation and inhibiting 5-HT-induced constriction of isolated rabbit basilar artery. The inhibition of uptake and enhancement of the release of 5-HT from brain synaptosomes indicates its ability to affect neuronal transmission in serotoninergic neurons. The effects of nicergoline are probably involved in the realization of its antimigraine action.

Animals↗
PubMed2002

Microemulsion cyclosporin inhibits vascular remodelling and attenuates associated changes in profibrotic gene expression in an experimental model of allograft vasculopathy.

BACKGROUND: Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterized by histological evidence of extracellular matrix (ECM) accumulation (fibrosis). The aim of this study was to characterize the changes in fibrosis-associated gene expression in an experimental model of CAD and to measure the effect of the immunosuppressant cyclosporin on these changes. METHODS: Lewis recipients of F344 rat thoracic to abdominal transplants were administered cyclosporin or no treatment. Vascular remodelling and ECM accumulation (picrosirius red) were measured using computerized histomorphometry. Fibrosis-associated gene expression was studied by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: Cyclosporin inhibited medial ECM accumulation and vascular remodelling in allografts. This was associated with an attenuation of the graft inflammatory infiltrate and a reduction in intragraft matrix metalloproteinase (MMP) 2 and MMP-9 messenger RNA (mRNA) levels. There was a significant negative correlation between neoadventitial ECM density and MMP-9 expression, as well as with vessel circumference. Neoadventitial ECM density was significantly higher in the cyclosporin-treated group than in animals with untreated allografts, as were mRNA levels of collagen 3 and tissue inhibitor of metalloproteinase 1. CONCLUSION: The alloimmune injury itself may contribute directly to vascular remodelling and fibrosis in allograft vasculopathy. Cyclosporin attenuated this component of the pathophysiology of CAD effectively.

Animals↗