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1.
Neuroscience ; 185: 97-105, 2011 Jun 30.
Article in English | MEDLINE | ID: mdl-21536110

ABSTRACT

Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca(2+) levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation.


Subject(s)
Cerebral Cortex/enzymology , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Glutamate-Ammonia Ligase/metabolism , Oxidative Stress/physiology , Analysis of Variance , Animals , Calcium/metabolism , Chromatography, High Pressure Liquid/methods , Disease Models, Animal , Electrophoresis, Gel, Two-Dimensional , Encephalitis/pathology , Encephalomyelitis, Autoimmune, Experimental/etiology , Female , Glutamate-Ammonia Ligase/analysis , Glutamic Acid/metabolism , Glutamine/metabolism , Glutathione/metabolism , Glutathione Disulfide/metabolism , Guinea Pigs , Mice , Myelin Basic Protein/adverse effects , Myelin Basic Protein/immunology , NAD/metabolism , NADP/metabolism , Nitric Oxide Synthase Type II/metabolism , Tandem Mass Spectrometry/methods
2.
J Neurovirol ; 7(6): 518-27, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11704884

ABSTRACT

To examine whether induction of apoptosis plays a role in the pathogenesis of street rabies, we compared the distribution of viral antigens, histopathology, and the induction of apoptosis in the brain of mice infected with a street rabies virus (silver-haired bat rabies virus, SHBRV) and with a mouse-adapted laboratory rabies virus strain (challenge virus standard, CVS-24). Inflammation was identified in the meninges, but not in the parenchyma of the brain of mice infected with either CVS-24 or SHBRV. Necrosis was present in numerous cortical, hippocampal, and Purkinje neurons in CVS-24-infected mice, but only minimal necrosis was identified in mice infected with SHBRV. Likewise, extensive terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining was observed in the brain of mice infected with CVS-24 but little or none in the brain of mice infected with SHBRV. Rabies virus antigens were distributed similarly in the CNS infected with either virus. However, the expression of the glycoprotein (G) is more widespread and the staining of G is generally stronger in CVS- than SHBRV-infected mice, whereas the expression of rabies virus nucleoprotein (N) is similar in mice infected with either CVS or SHBRV. The positive TUNEL staining thus correlates with the high level of G expression in CVS-infected mouse brain. Northern blot hybridization revealed that the ratio between the N and G transcripts is similar in brains infected with either virus, indicating that the reduced expression of G protein is not caused by reduced transcription in SHBRV-infected animals. Taken together, these observations suggest that apoptosis is not an essential pathogenic mechanism for the outcome of a street rabies virus infection and that other pathologic processes may contribute to the profound neuronal dysfunction characteristic of street rabies.


Subject(s)
Antigens, Viral , Apoptosis , Brain/virology , Rabies virus/pathogenicity , Rabies/pathology , Animals , Blotting, Northern , Brain/pathology , Chiroptera , Glycoproteins/genetics , In Situ Nick-End Labeling , Mice , Mice, Inbred ICR , Necrosis , Neurons/pathology , Neurons/virology , Nucleocapsid/genetics , Nucleocapsid Proteins , RNA, Messenger/analysis , Viral Envelope Proteins/genetics , Virulence
3.
Neurosurgery ; 45(5): 1239-42; disscussion 1242-3, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10549944

ABSTRACT

OBJECTIVE AND IMPORTANCE: Neurenteric cysts are very rare (particularly in the adult age group) congenital intraspinal cysts of endodermal origin. The patient described was a 48-year-old man who was diagnosed as having an isolated thoracic neurenteric cyst at the T5-T6 level, without a mediastinal enterogenous cyst. Radiological studies demonstrated multiple anterior vertebral column abnormalities. CLINICAL PRESENTATION: The patient presented with a long history of mild midback pain. During the 2 years preceding admission, his midback pain worsened and he experienced right intercostal pain in the midthoracic area. Several months before admission, he noticed right lower extremity weakness, which led him to undergo neurological evaluation and radiological studies. INTERVENTION: Thoracic spine x-rays revealed marked thoracic scoliosis and multiple vertebral abnormalities. Magnetic resonance imaging and myelography revealed an intradural extramedullary cystic mass at the T5-T6 level, severely compressing the spinal cord from the ventral side. Thoracic laminectomy was performed and the cystic lesion was completely removed, with disconnection of the ventral tract. CONCLUSION: This is an unusual presentation, at this age, of a congenital intraspinal cyst in the thoracic area. Such cysts must investigated for early diagnosis and treatment. A neurenteric cyst should be suspected particularly if the cyst is associated with anterior vertebral column abnormalities.


Subject(s)
Spina Bifida Occulta/surgery , Thoracic Vertebrae/abnormalities , Adult , Diagnostic Imaging , Humans , Laminectomy , Male , Middle Aged , Spina Bifida Occulta/diagnosis , Spina Bifida Occulta/pathology , Spinal Cord Compression/diagnosis , Spinal Cord Compression/pathology , Spinal Cord Compression/surgery , Thoracic Vertebrae/pathology , Thoracic Vertebrae/surgery
4.
Neurology ; 45(11): 2042-50, 1995 Nov.
Article in English | MEDLINE | ID: mdl-7501157

ABSTRACT

Gerstmann-Sträussler-Scheinker disease (GSS) is caused by several different point mutations of the prion protein (PrP) gene, each of which generally produces a distinct clinical phenotype. An ataxic form of GSS is genetically linked to a mutation at codon 102 (CCG-->CTG) leading to the substitution of leucine for proline, while a "telencephalic" variant of GSS, in which dementia is the predominant symptom and ataxia is minimal, has been described in two kindreds with a mutation at codon 117 (GCA-->GTG) resulting in the substitution of valine for alanine. In this report, we present a family with ataxic GSS that has, however, the same mutation at codon 117 as is present in the telencephalic variant of GSS. Other than an additional silent mutation (GCA-->GCG) at codon 117 on the normal allele, there were no other mutations detected. At the polymorphic codon 129, valine was encoded by both alleles in the proband that we studied. Why this family with prion disease (PrP-A117V) should present with ataxia instead of dementia, which was found in two previously identified families with the same PrP gene mutation, remains to be established.


Subject(s)
Ataxia/physiopathology , Prion Diseases/genetics , Prion Diseases/physiopathology , Adult , Base Sequence , DNA/analysis , Dementia/physiopathology , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Male , Molecular Sequence Data , Polymerase Chain Reaction , Prion Diseases/pathology
5.
Neurosurgery ; 35(6): 1163-7, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7885566

ABSTRACT

We present a case of isolated carcinoid tumor of the sacrum and highlight the unusual nature of this lesion. The histopathology suggests hindgut cause, and we discuss the possibility of an underlying congenital tailgut cyst. We review the pathology of these rare anomalies with reference to embryological development and known instances of carcinoid focus. We also present previous reports of sacral carcinoid.


Subject(s)
Carcinoid Tumor/surgery , Sacrum/surgery , Spinal Neoplasms/surgery , Biomarkers, Tumor/analysis , Carcinoid Tumor/diagnosis , Carcinoid Tumor/embryology , Carcinoid Tumor/pathology , Humans , Immunoenzyme Techniques , Magnetic Resonance Imaging , Male , Microscopy, Electron , Middle Aged , Sacrum/embryology , Sacrum/pathology , Spinal Neoplasms/diagnosis , Spinal Neoplasms/embryology , Spinal Neoplasms/pathology , Tomography, X-Ray Computed
6.
Am J Med Genet ; 53(3): 251-4, 1994 Nov 15.
Article in English | MEDLINE | ID: mdl-7856661

ABSTRACT

Non-immune hydrops fetalis (NIHF) is due to many different causes. Fetal hypomobility has been alluded to as a possible cause. We present a preterm fetus with NIHF secondary to fetal hypomobility. Fetal movements were undetected after the 20th week of gestation. The infant was born 8 weeks later and was edematous, had pleural effusions, and no spontaneous movements. He died on day four of life. Diffuse massive central nervous system (CNS) destruction found on post-mortem examination was thought to be the origin of the hypomobility. As all other causes of NIHF were eliminated, we propose that the NIHF in this infant was due to the hypomobility. This case then gives support to the assertion that fetal hypomobility is another cause of NIHF. The cause of the CNS catastrophy remains unelucidated.


Subject(s)
Fetal Movement , Hydrops Fetalis/etiology , Infant, Premature, Diseases/etiology , Brain/abnormalities , Fatal Outcome , Humans , Infant, Newborn , Male , Movement Disorders/complications
8.
J Neurosurg ; 79(5): 756-60, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8410256

ABSTRACT

The authors report a 32-year-old woman who had undergone repair of an occipital encephalocele in infancy and who experienced a 20-year history of progressive hearing loss and intermittent vertigo. After parturition, she developed a rapidly progressive quadriparesis and brain-stem dysfunction associated with persistent intraventricular and subarachnoid hemorrhage. Serial magnetic resonance (MR) images showed progressive deposition of hemosiderin along the surface of the brain, brain stem, and spinal cord, and enhanced thickened membranes at the site of the original encephalocele repair. Posterior fossa exploration disclosed hemorrhagic membranes, which were resected; despite removal of this tissue, the patient deteriorated and died. Postmortem examination confirmed iron-containing pigment along the meninges, cerebral hemispheres, brain stem, spinal cord, and cranial nerves accompanied by atrophy of the superficial cerebellar cortex. It is concluded that superficial siderosis may accompany encephalocele repair. This is believed to be the first report in the literature of superficial siderosis of the central nervous system to correlate in vivo MR images with autopsy results.


Subject(s)
Central Nervous System Diseases/diagnosis , Siderosis/diagnosis , Adult , Central Nervous System Diseases/pathology , Cerebellum/pathology , Cranial Fossa, Posterior , Encephalocele/surgery , Female , Humans , Magnetic Resonance Imaging , Postoperative Complications , Siderosis/pathology
9.
J Clin Neuroophthalmol ; 12(4): 250-6, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1287050

ABSTRACT

We report a patient who rapidly developed unilateral proptosis and complete ophthalmoplegia following blunt trauma to the orbit. Computed tomography (CT) scan revealed a mass involving the sinuses and orbit with erosion of the cribriform plate. Biopsy of this suspected neoplasm revealed features consistent with allergic Aspergillus sinusitis, but cultures later grew a Bipolaris species. Our review of the literature suggests that when allergic fungal sinusitis involves the orbit, Bipolaris is a more commonly isolated organism than Aspergillus. Additionally, extraocular motility impairment and proptosis occur more frequently than visual loss. Treatment is controversial, but surgical drainage followed by corticosteroids is the most often recommended therapy.


Subject(s)
Cellulitis/microbiology , Eye Infections, Fungal , Mitosporic Fungi , Orbital Diseases/microbiology , Adult , Cellulitis/diagnostic imaging , Eye Infections, Fungal/diagnostic imaging , Humans , Male , Orbital Diseases/diagnostic imaging , Radiography
10.
Obstet Gynecol ; 79(1): 111-6, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1727568

ABSTRACT

There are recent reports of postmenopausal bleeding from endometrial polyps in women receiving tamoxifen therapy for breast cancer. We describe four additional patients who presented with vaginal bleeding, and emphasize the pathology. These polyps demonstrated cystically dilated glands in all cases and stromal decidualization in two; in one instance, metastatic breast carcinoma was present in the polyp. The mechanisms by which tamoxifen may affect the development of these polyps are discussed.


Subject(s)
Endometrial Neoplasms/chemically induced , Polyps/chemically induced , Tamoxifen/adverse effects , Uterine Hemorrhage/etiology , Aged , Breast Neoplasms/drug therapy , Endometrial Neoplasms/complications , Endometrial Neoplasms/pathology , Female , Humans , Menopause , Middle Aged , Polyps/complications , Polyps/pathology , Tamoxifen/therapeutic use
11.
Arch Biochem Biophys ; 236(2): 638-45, 1985 Feb 01.
Article in English | MEDLINE | ID: mdl-2982320

ABSTRACT

Mitoplasts were prepared from 3-h ischemic livers in an attempt to define the structural alterations in the inner membrane that may account for the functional deficiencies of ischemic mitochondria. Mitoplasts from both control and ischemic livers had similar specific activities of cytochrome oxidase and succinate-cytochrome c reductase. With both preparations, the specific activity of rotenone-insensitive NADH-cytochrome c reductase was 10-fold lower than in the mitochondria from which they were prepared. Ischemic mitoplasts had no respiratory control with ADP, and had a slightly reduced phospholipid to protein ratio and an increased cholesterol to protein ratio. As a result, the cholesterol to phospholipid molar ratio was increased from the control of 0.04 to 0.08. There were also differences in the content of individual phospholipid species. Phosphatidylcholine increased by 15%, while cardiolipin decreased by 60%. There were increases in sphingomyelin and in the lysophospholipids of phosphatidylcholine, ethanolamine, and cardiolipin. Pretreatment with chlorpromazine did not prevent these changes. Linoleic acid was decreased by 35% in ischemic phospholipids, and the content of free fatty acids was increased 4-fold. Electron spin resonance spectroscopy of mitoplasts spin labeled with either 5- or 12-doxyl stearic acid revealed an increased molecular order (decreased fluidity) of ischemic inner mitochondrial membranes consistent with the increased cholesterol to phospholipid ratio. The data indicate activation of a phospholipase A in ischemic mitochondria with the resulting accumulation of products of lipid hydrolysis. This conclusion further emphasizes the close similarity between the structural and functional consequences of ischemia in the intact animal and the effect on isolated mitochondria of the activation of the endogenous phospholipase A. In both cases the major functional alterations are attributable to changes in the permeability of the inner mitochondrial membrane induced by the accumulation of lysophospholipids.


Subject(s)
Intracellular Membranes/pathology , Ischemia/pathology , Liver/blood supply , Mitochondria, Liver/pathology , Animals , Electron Transport Complex IV/metabolism , Female , Ischemia/enzymology , Ischemia/metabolism , Membrane Lipids/metabolism , Mitochondria, Liver/enzymology , Mitochondria, Liver/metabolism , NADH Dehydrogenase/metabolism , Oxygen Consumption , Phospholipids/metabolism , Rats , Rats, Inbred Strains , Succinate Cytochrome c Oxidoreductase/metabolism
12.
Arch Biochem Biophys ; 235(2): 644-9, 1984 Dec.
Article in English | MEDLINE | ID: mdl-6097193

ABSTRACT

The effect of enzymatic lipid peroxidation on the molecular order of microsomal membranes was evaluated by ESR spectroscopy using the spin probes 5-, 12-, and 16-doxyl-stearic acid. Rat liver microsomal membranes were peroxidized by the NADPH-dependent reaction in the presence of the chelate ADP-Fe3+. Peroxidation resulted in a preferential depletion of polyenoic fatty acids and an increase in the percentage composition of shorter fatty acyl chains. There was no change in the cholesterol/phospholipid ratio of the peroxidized microsomes. The molecular order of both control and peroxidized membranes decreased toward the central region of the bilayer, and the order parameter (S) of each probe was temperature dependent. Peroxidation of the microsomal membrane lipids resulted in an increase in the order parameter determined with the three stearic acid spin probes. Of the three probes, 12-doxylstearic acid was the most sensitive to the changes in membrane organization caused by peroxidation. These data indicate that ESR spectroscopy is a sensitive method of detecting changes in membrane order accompanying peroxidation of membrane lipids.


Subject(s)
Lipid Peroxides/biosynthesis , Membrane Lipids/metabolism , Microsomes, Liver/metabolism , Animals , Chemical Phenomena , Chemistry , Electron Spin Resonance Spectroscopy , Fatty Acids/analysis , Female , In Vitro Techniques , Molecular Conformation , NADP/metabolism , Rats , Rats, Inbred Strains , Temperature
13.
Am J Pathol ; 117(2): 163-6, 1984 Nov.
Article in English | MEDLINE | ID: mdl-6541879

ABSTRACT

The role of alterations in the cytoskeleton in the anoxic death of cultured hepatocytes was evaluated with the use of cytochalasin B and colchicine. The addition of 50 microM Cytochalasin did, however, reduce the rate of accumulation of dead cells but was without effect on the number of cells that died. After 6 hours of anoxia in the presence of cytochalasin, 80% of the cells were dead. The same number of cells were dead after 4 hours in the absence of cytochalasin. Colchicine was without effect on the cell killing by anoxia. Cytochalasin also did not prevent the increase in the molecular order of the membranes of the anoxic hepatocytes as determined by electron spin resonance spectroscopy. In the presence or absence of cytochalasin, anoxia increased the order parameter, S, of hepatocytes spin-labeled with 12-doxyl stearic acid. These data indicate that changes in the organization of microfilaments that can be prevented by cytochalasin may aggravate the mechanisms mediating the anoxic death of the hepatocytes, but such mechanisms are essentially independent of these alterations in the cytoskeleton. The data do not exclude from a role in anoxic cell death other cytoskeletal changes that may not be affected by either cytochalasin or colchicine.


Subject(s)
Cytochalasin B/pharmacology , Hypoxia/pathology , Liver/pathology , Adenosine Triphosphate/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Cytoskeleton/pathology , Kinetics , Liver/metabolism , Membrane Fluidity/drug effects , Phospholipids/metabolism , Rats , Rats, Inbred Strains
14.
Proc Soc Exp Biol Med ; 173(1): 76-81, 1983 May.
Article in English | MEDLINE | ID: mdl-6304745

ABSTRACT

Endogenous opiates have been reported to have detrimental effects on the circulatory system during hemorrhagic shock. However, the specific opiate receptor subtype which mediates these actions has not been defined. In the present study, we have utilized the mixed agonist/antagonist, nalorphine (N-allylnormorphine), which exhibits kappa (kappa) and sigma (sigma) receptor agonism as well as mu (mu) receptor antagonism, to investigate the role of the mu receptor in hemorrhagic shock. Nalorphine (2 mg/kg) produced no significant changes in any observed experimental variable in sham-shocked animals. Shocked animals treated with nalorphine (2 mg/kg) maintained significantly higher final mean arterial blood pressures (MABP) than animals which received only vehicle (102 +/- 3.8 vs 61 +/- 6.6 mm Hg, respectively, p less than 0.001). In addition, nalorphine significantly reduced the rise in plasma MDF activity observed in untreated hemorrhaged animals (42 +/- 3.0 vs 59 +/- 4 U/ml, p less than 0.02). Our results support a significant role for the mu receptor in the deleterious actions of endogenous opioids during hemorrhagic shock.


Subject(s)
Nalorphine/therapeutic use , Shock, Hemorrhagic/drug therapy , Animals , Blood Pressure/drug effects , Cathepsin D , Cathepsins/blood , Cats , Male , Myocardial Contraction/drug effects , Myocardial Depressant Factor/blood , Receptors, Opioid/drug effects , Shock, Hemorrhagic/physiopathology
15.
Gen Pharmacol ; 14(2): 265-7, 1983.
Article in English | MEDLINE | ID: mdl-6404693

ABSTRACT

1. Experiments were undertaken to examine the hemodynamic effects of intravenously administered leucine and methionine enkephalin and to determine if prostaglandin synthesis is involved in these responses. 2. Intravenous administration of leucine and methionine enkephalin (10, 30 and 100 micrograms/kg) resulted in a dose dependent and transient decline in mean arterial blood pressure in pentobarbital anesthetized cats. 3. A significant difference was observed, however, between the hemodynamic responses to leucine and methionine enkephalins before sodium meclofenamate (1 mg/kg) administration compared to post-meclofenamate induced hemodynamic changes. 4. This was confirmed with ibuprofen. 5. These findings indicate that cyclooxygenase inhibition modulates the circulatory responses to enkephalins. 6. Since cyclooxygenase is the first enzyme in the biosynthetic pathway of arachidonic acid, it is possible that prostaglandins, endoperoxides, thromboxanes or other prostanoids may be involved in mediating the circulatory responses to enkephalins.


Subject(s)
Cyclooxygenase Inhibitors , Enkephalins/pharmacology , Hemodynamics/drug effects , Animals , Blood Pressure/drug effects , Cats , Enkephalin, Leucine/pharmacology , Enkephalin, Methionine/pharmacology , Male , Meclofenamic Acid/pharmacology , Prostaglandins/biosynthesis , Splanchnic Circulation/drug effects
16.
Adv Shock Res ; 10: 101-9, 1983.
Article in English | MEDLINE | ID: mdl-6308972

ABSTRACT

The protective effect exerted by opiate antagonists in hemorrhagic shock appears to involve blockade of endogenous opioid substances at opiate receptors. The existence of several types of opiate receptors has been proposed. Previous work has shown that mu and delta opiate receptors may be involved in the shock process, but that k receptors appear not to be critically involved in the pathogenesis of shock. Administration of the potent k receptor agonist ethylketocyclazocine to hemorrhaged cats resulted in significant improvement in final mean arterial blood pressure and significant improvement in final plasma MDF activities compared to hemorrhaged cats given only vehicle. These data indicate that k receptor activation does not exacerbate the shock state, thus supporting the hypothesis that k receptors are not involved in the development of circulatory shock. Ethylketocyclazocine may act as an antagonist at the epsilon opiate receptor, indicating possible involvement of this receptor type in the pathogenesis of circulatory shock.


Subject(s)
Cyclazocine/analogs & derivatives , Shock, Hemorrhagic/drug therapy , Animals , Blood Pressure/drug effects , Cathepsin D , Cathepsins/blood , Cats , Cyclazocine/administration & dosage , Ethylketocyclazocine , Male , Myocardial Depressant Factor/blood , Receptors, Opioid/drug effects , Shock, Hemorrhagic/etiology , Shock, Hemorrhagic/physiopathology
18.
Circ Shock ; 10(2): 131-45, 1983.
Article in English | MEDLINE | ID: mdl-6301706

ABSTRACT

The broad-spectrum opiate antagonist naloxone has been shown previously to reverse hypotension and improve survival in hemorrhaged animals. Three new opiate antagonists with different receptor affinities and activities were utilized to investigate the role of the "mu"- and "kappa"-receptors in hemorrhagic shock. Cats in hemorrhagic shock (40 mm Hg for 150 min) and shamshock controls were given J-7747 (delta-antagonist), C-7000 (delta-antagonist and k-agonist) or MR-2266 (k-antagonist). Shock cats given the delta-antagonist J-7747 had a significantly higher final MABP than cats given vehicle as did the cats given C-7000, the delta-antagonist k-agonist. However, the k-antagonist MR-2266 did not result in a significantly greater MABP than untreated hemorrhaged cats. Both J-7747 and C-7000 significantly prevented the increase in plasma MDF activity observed in untreated shock cats, but MR-2266 did not. These results indicate that opiate receptors other than at k-receptor sites are involved in the pathophysiology of hemorrhagic shock. Our findings also introduce the possibility of the therapeutic use of opiate antagonist-analgesics that induce analgesia via the kappa receptor.


Subject(s)
Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Receptors, Opioid/drug effects , Shock, Hemorrhagic/physiopathology , Animals , Benzomorphans/analogs & derivatives , Benzomorphans/pharmacology , Blood Pressure/drug effects , Blood Urea Nitrogen , Cathepsin D , Cathepsins/blood , Cats , Lysosomes/enzymology , Male , Mice , Myocardial Depressant Factor/blood , Peptide Hydrolases/metabolism
19.
Eur J Pharmacol ; 78(3): 307-13, 1982 Mar 12.
Article in English | MEDLINE | ID: mdl-6279411

ABSTRACT

The new opiate antagonist Win 44,441-3 (-)-isomer was infused intravenously in cats at a rate of 2 mg . kg-1 . h-1 to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with Win 44,441-3 maintained post reinfusion mean arterial blood pressure (MABP) at a higher value compared to cats receiving only the vehicle. Final MABP was 70 +/- 11 mm Hg for cats receiving vehicle compared to 103 +/- 7 mm Hg for cats receiving Win 44,441-3. These values represent 60 +/- 9% and 85 +/- 6% of initial MABP for the vehicle- and Win 44,441-3-treated cats respectively. Win 44,441-2 (+)-isomer, the inactive stereoisomer of Win 44,441-3, was also infused at 2 mg . kg-1 . h-1 in cats subjected to hemorrhagic shock. The final pressure in this group was 72 +/- 8 mm Hg which is 61 +/- 8% of the initial pressure for this group. Win 44,441-3 and Win 44,441-2 were both ineffective in moderating increases in circulating lysosomal hydrolase activity in shocked cats. Neither isomer stabilized lysosomal membranes or retarded proteolysis in vitro. Plasma myocardial depressant factor was significantly reduced by the opiate antagonist, Win 44,441-3 during shock. Our results show that the systemic infusion of an opiate antagonist improves the hemodynamic state of cats subjected to hemorrhagic shock while the (+)-isomer which lacks opiate antagonist activity produces no such improvement.


Subject(s)
Azocines , Benzomorphans/therapeutic use , Morphinans/therapeutic use , Narcotic Antagonists/therapeutic use , Shock, Hemorrhagic/drug therapy , Animals , Benzomorphans/analogs & derivatives , Blood Pressure/drug effects , Cathepsin D , Cathepsins/metabolism , Cats , Liver/metabolism , Male , Myocardial Depressant Factor/blood , Naloxone/pharmacology , Receptors, Opioid/metabolism , Shock, Hemorrhagic/physiopathology , Time Factors
20.
Arch Int Pharmacodyn Ther ; 255(1): 48-58, 1982 Jan.
Article in English | MEDLINE | ID: mdl-7073399

ABSTRACT

Tissue uptake and plasma levels of 3H-naloxone were studied in normotensive control cats, as well as in hemorrhagic hypotensive cats. Intravenous injection of naloxone resulted in a rapid and extensive uptake of naloxone label from plasma by several tissues. Plasma half-life of the radiolabel was determined to be 137 min. One and two hours after injection, large amounts of naloxone label were found in the liver, pancreas, adrenal, kidney and lung, with tissue/plasma ratios ranging from 2 to 30. Brain tissue displayed the lowest tissue/plasma ratios of any organ sampled. Infusion of 8 mg/kg -1.hr-1 naloxone resulted in an increase in concentration of radiolabel over a 2 hr period. Hemorrhagic shock did not significantly retard uptake of naloxone by tissues. Splanchnic organs displayed high uptake of naloxone even during hemorrhagic shock. Brain tissue in cats subjected to hemorrhagic shock had the lowest uptake naloxone of all tissues sampled. The degree of uptake of naloxone by tissues is consistent with its proposed role in lysosomal membrane stabilization and prevention of proteolysis during hemorrhagic shock.


Subject(s)
Naloxone/metabolism , Shock, Hemorrhagic/metabolism , Animals , Cats , Hemodynamics/drug effects , Kinetics , Male , Naloxone/pharmacology , Time Factors , Tissue Distribution
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