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PubMed2002

Kupffer cells protect liver from ischemia-reperfusion injury by an inducible nitric oxide synthase-dependent mechanism.

The aim of this study was to investigate the role of nitric oxide (NO) in rat hepatic ischemia-reperfusion (I/R) injury. Animals were divided into four groups: Group I, control; Group II, gadolinium chloride (GdCl3), a Kupffer cell depleting agent, pretreated; Group III, S-methylisothiourea (SMT), a potent inducible NO synthase (iNOS) inhibitor, pretreated; Group IV, pretreated with SMT, then treated with S-Nitroso-N-acetylpenicillamine (SNAP), a NO donor, after ischemia. Sprague-Dawley rats underwent left lateral and median lobe ischemia for 60 min and reperfusion for 120 min. The left lateral and median lobes were used as ischemic lobes, and the right lateral lobe in the same rat was used as a control lobe. The total NOS (tNOS), iNOS, constitutive NOS (cNOS) activity, and liver protein were determined. The liver tissue malonaldehyde (MDA) level was measured as an index of lipid peroxidation. Liver histology was also examined. The liver tNOS activity in ischemic lobes of Group I, II, III, and IV was increased by 214%, 86%, 61%, and 45%, respectively. The increase in tNOS activity is mainly due to the induction of iNOS activity in the ischemic lobes of rat liver. GdCl3 significantly decreased the tNOS by 66% in the ischemic lobes. GdCl3 significantly increased MDA by 39% in the ischemic lobes. SMT significantly decreased tNOS and iNOS activity by 66% and 85% in ischemic lobes. SMT increased MDA by 67% in the ischemic lobes. SMT + SNAP treatment increased iNOS activity by 117% in the ischemic lobes in comparison with the ischemic lobes of the SMT group. SMT + SNAP treatment decreased MDA by 39% in the ischemic lobes. SMT + SNAP treatment also decreased the sinusoidal congestion and spotty necrosis of hepatocytes in the ischemic lobes. iNOS immunostaining showed an obvious increase in sinusodial area of the ischemic lobes where most Kupffer cells were interspersed. In conclusion, in this model of liver I/R injury, I/R increased the activity of tNOS and iNOS, but not the cNOS activity. Kupffer cells might be the major source of the induction of iNOS activity. The iNOS specific inhibitor SMT increased the lipid peroxidation and the tissue damage in hepatic I/R injury. On the contrary, the NO donor SNAP increased the activity of iNOS and decreased the hepatic injury in this study. Kupffer cells could protect liver from I/R injury by an iNOS-dependent mechanism, thus NO production has a beneficial role in hepatic IR injury.

Animals↗
PubMed2004

Hypertonic saline-enhanced postburn gut barrier failure is reversed by inducible nitric oxide synthase inhibition.

OBJECTIVE: To determine whether inhibition of inducible nitric oxide synthase to stabilize endothelial permeability and to retain hypertonic saline in the vascular space will ameliorate burn-induced gut barrier dysfunction. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university hospital. SUBJECTS: Thermal injury models in the rat. INTERVENTIONS: In experiment 1, specific pathogen free rats underwent 3% total body surface area burn or sham burn and were given 7.5 mL/kg hypertonic saline (7.5% NaCl), 7.5 mg/kg saline, or 50 mL/kg saline (nearly equal sodium load with hypertonic saline) in the right femoral vein for 15 mins for fluid resuscitation at 0, 4, or 8 hrs after burn. In experiment 2, S-methylisothiourea (7.5 mg/kg, intraperitoneally), a specific inducible nitric oxide synthase inhibitor, was given immediately after burn to rats from different groups as in experiment 1. At 24 hrs after burn, the intestinal mucosa was assayed for myeloperoxidase activity and lipid peroxidation, the distribution of fluorescein isothiocyanate-dextran across the lumen of the small intestine was determined, and bacterial translocation to the mesenteric lymph nodes and ileum histology were also examined. MEASUREMENTS AND MAIN RESULTS: Burn induced significant increases in intestinal mucosa inducible nitric oxide synthase expression, myeloperoxidase activity, lipid peroxidation, intestinal permeability, bacterial translocation to mesenteric lymph nodes, and villi sloughing in rats. Hypertonic saline administration at 0 or 4 hrs after burn worsened intestinal mucosa lipid peroxidation, neutrophil sequestration, intestinal permeability, and villi sloughing compared with those of burn + 7.5 mg/kg saline and burn + 50 mL/kg saline rats. To the contrary, burn + S-methylisothiourea rats with hypertonic saline injection at 4 or 8 hrs after burn showed an improvement of gut barrier function compared with burn + S-methylisothiourea + 7.5 mg/kg saline and burn + S-methylisothiourea + 50 mL/kg saline rats. Administration of hypertonic saline at 8 hrs after burn and S-methylisothiourea injection also significantly attenuated the bacterial translocation to mesenteric lymph nodes and villi sloughing. CONCLUSIONS: Using hypertonic saline as a resuscitation fluid in early burn shock markedly augmented the thermal injury-induced intestinal mucosa neutrophil deposition, lipid peroxidation, and intestinal hyperpermeability. Inhibition of inducible nitric oxide synthase not only significantly attenuated neutrophil deposition and mucosa lipid peroxidation but also reversed the deteriorating effects of hypertonic saline on thermal injury-induced gut barrier dysfunction and bacterial translocation.

Animals↗
PubMed2005

Inducible nitric oxide synthase inhibition potentiates multiple organ dysfunction induced by endotoxin in conscious rats.

This study was designed to investigate the effects of inducible nitric oxide synthase (iNOS) inhibition with S-methylisothiourea (SMT) and L-N-(1-iminoethyl)-lysine (L-Nil) on the endotoxemia induced by intravenous lipopolysaccharide (LPS, 10 mg/kg) in conscious rats. Arterial pressure (AP), heart rate (HR), WBC, platelets, plasma nitrite/nitrate, tumor necrosis factor alpha (TNF alpha), and biochemical factors were measured for 24 hours after LPS with or without iNOS inhibitors. RT-PCR was employed to determine the iNOS and endothelial NOS (eNOS) mRNA. Pathologic examinations of the liver and heart were performed. SMT and L-Nil improved the systemic hypotension and increased the HR after LPS. These agents attenuated the LPS-induced leukocytopenia and thrombocytopenia and the increase in nitrite/nitrate. However, iNOS inhibition aggravated the LPS-induced changes in TNF alpha, all biochemical factors, and the hepatic and cardiac tissue damage. The iNOS mRNA, but not the eNOS, was reduced. Our results in conscious rats indicate that iNOS inhibition enhances the organ dysfunction and tissue damage in sepsis. The discrepancy may be attributed to the method for evaluating the sepsis and the effects of anesthesia. Further investigation is required to ensure the effects of iNOS inhibition on sepsis before iNOS inhibitors can be applied in clinical cases with sepsis.

Animals↗
PubMed2003

Involvement of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis in rats.

PURPOSE: We evaluated the relationship between nitric oxide and hyperbaric oxygenation in the pathogenesis and treatment of cyclophosphamide induced hemorrhagic cystitis in rats. MATERIALS AND METHODS: Cyclophosphamide (100 mg/kg) was injected in male Sprague-Dawley rats for cystitis induction. Animals were treated before and the day after cyclophosphamide injection with 100 mg/kg of the nitric oxide substrate L-arginine, 20 mg/kg of the nonselective nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester and 20 mg/kg of the selective inducible nitric oxide synthase inhibitor S-methylisothiourea. Animals were exposed to hyperbaric oxygen (2.8 atmospheres absolute for 90 minutes twice daily) with or without the administration of L-arginine and nitric oxide synthase inhibitors. RESULTS: Cyclophosphamide injection resulted in severe cystitis. S-methylisothiourea produced marked inhibition of cyclophosphamide induced bladder tissue damage. L-arginine and L-NG-nitroarginine methyl ester failed to a show meaningful protective effect. Hyperbaric oxygen protected the bladder only against ulceration. Moreover, hyperbaric oxygen did not contribute to the protective effects of L-arginine, L-NG-nitroarginine methyl ester or S-methylisothiourea. CONCLUSIONS: Nitric oxide produced by inducible nitric oxide synthase is an important mediator in the pathogenesis of cyclophosphamide induced cystitis. Hyperbaric oxygen has a beneficial effect on repairing bladder damage rather than on bladder protection.

Animals↗
PubMed2006

Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia.

The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 mug/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFkappaB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.

Animals↗
PubMed2003

Modulation of nerve growth factor-induced activation of MAP kinase in PC12 cells by inhibitors of nitric oxide synthase.

Nerve growth factor (NGF) increases expression of nitric oxide synthase (NOS) isozymes leading to enhanced production of nitric oxide (NO). NOS inhibitors attenuate NGF-mediated increases in cholinergic gene expression and neurite outgrowth. Mechanisms underlying this are unknown, but the mitogen-activated protein (MAP) kinase pathway plays an important role in NGF signaling. Like NGF, NO donors activate Ras leading to phosphorylation of MAP kinase. The present study investigated the role of NO in NGF-mediated activation of MAP kinase in PC12 cells. Cells were treated with 50 ng/mL NGF to establish the temporal pattern for rapid and sustained activation phases of MAP kinase kinase (MEK)-1/2 and p42/p44-MAP kinase. Subsequently, cells were pretreated with NOS inhibitors Nomega-nitro-L-arginine methylester and s-methylisothiourea and exposed to NGF for up to 24 h. NGF-induced activation of MEK-1/2 and p42/p44-MAP kinase was not dependent on NO, but sustained phosphorylation of MAP kinase was modulated by NO. This modulation did not occur at the level of Ras-Raf-MEK signaling or require activation of cGMP/PKG pathway. NOS inhibitors did not affect NGF-mediated phosphorylation of MEK. Expression of constitutively active-MEKK1 in cells led to phosphorylation of p42/p44-MAP kinase and robust neurite outgrowth; constitutively active-MKK1 also caused differentiation with neurite extension. NOS inhibitor treatment of cells expressing constitutively active kinases did not affect MAP kinase activation, but neurite outgrowth was attenuated. NOS inhibitors did not alter NGF-mediated nuclear translocation of phospho-MAP kinase, but phosphorylated kinases disappeared more rapidly from NOS inhibitor-treated cells suggesting greater phosphatase activity and termination of sustained activation of MAP kinase.

Animals↗
PubMed1986

Isothiouronium compounds as gamma-aminobutyric acid agonists.

Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites.

4-Aminobutyrate Transaminase↗
PubMed1994

Characterization of the binding of the first selective radiolabelled histamine H3-receptor antagonist, [125I]-iodophenpropit, to rat brain.

1. The binding of the first selective radiolabelled histamine H3-receptor antagonist [125I]-iodophenpropit to rat cerebral cortex membranes was characterized. 2. [125I]-iodophenpropit, radiolabelled to a high specific activity of 1900 Ci mmol-1, saturably bound to a single class of sites with a KD of 0.57 +/- 0.16 nM (n = 4) and Bmax of 268 +/- 119 fmol mg-1 protein. 3. Specific binding at a concentration below 1 nM represented 50 to 60% of total binding. 4. Binding of [125I]-iodophenpropit to rat cerebral cortex membranes was readily displaced by histamine H3-agonists and antagonists. In contrast, the inhibitory potencies of selective histamine H1- and H2-receptor ligands were very low. 5. [125I]-iodophenpropit was biphasically displaced by the histamine H3-receptor antagonists, burimamide and dimaprit, which may indicate the existence of histamine H3-receptor subtypes. Other histamine H3-receptor antagonists showed a monophasic displacement. 6. Competition binding curves of H3-agonists were biphasic and showed a rightward shift upon the addition of the nonhydrolysable GTP analogue, guanosine 5'-o-(3-thio) triphosphate (GTP gamma S; 100 microM) which implicates the interaction of histamine H3-receptors with G-proteins. The affinities of the H3-receptor antagonists iodophenpropit, thioperamide and burimamide were not altered by GTP gamma S. 7. Histamine competition binding curves were shifted to the right by different nucleotides (100 microM) with a rank order of potency GTP gamma S > Gpp(NH)p, GTP. 8 In vitro autoradiographic studies revealed a heterogeneous distribution of [125I]-iodophenpropitbinding sites in rat brain, with highest densities observed in specific cerebral cortical areas and layers,the caudate-putamen complex, the olfactory tubercles, the hippocampal formation, the amygdala complex, the hypothalamic area and the mammillary bodies.9 It is concluded that the histamine H3-receptor antagonist, [125I]-iodophenpropit, meets the criteria fo ra suitable radioligand for histamine H3-receptor binding studies in rat brain.

Animals↗
PubMed1995

Interaction of clozapine with the histamine H3 receptor in rat brain.

We examined possible interactions between neuroleptics and the histamine H3 receptor and found an interaction of clozapine with this receptor. In competition binding experiments, using the H3 antagonist, [125I]-iodophenpropit, we observed a Ki of 236 +/- 87 nM. Functionally, clozapine was studied on the H3-mediated inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from rat brain cortex slices. Clozapine acts as an antagonist with an apparent KB value of 79.5 nM.

Animals↗
PubMed1995

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5-HT3 receptor revealed.

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. The interaction with the 5-HT3 receptor was not restricted to IPP or thioperamide, but was alsofound with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belongingto the same chemical class of IPP, also interacted with the 5-HT3 receptor (Ki = 240 +/- 40 nM). In contrast,histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor.7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in apD2 value of 4.72 +/- 0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 valueof 7.1 +/- 0.1 (n = 9). Similarly ondansetron antagonized the contractions evoked by the 5-HT3 receptoragonist, 2-methyl-5-HT with a pA2 value of 7.3 +/- 0.1 (n = 4). IPP and thioperamide did not mimic 2-methyl-5-HT but non-competitively inhibited the 2-methyl-5-HT-induced contractions of thispreparation.8 In an in vivo model for 5-HT3 activity, the Von Bezold Jarisch reflex, thioperamide showedantagonism in low dosages, which correlated well with the affinity for the 5-HT3 receptor site. Yet, athigher dosages no further 5-HT3 receptor antagonism was observed. For IPP no 5-HT3 receptor activitycould be observed in vivo.9 In the present study we showed that many H3 receptor compounds, that are regarded as highlyselective (including the prototype drug, thioperamide), also interact with the 5-HT3 receptor, albeit athigher drug concentrations.Keywords.: Histamine H3-receptor; iodophenpropit; thioperamide; receptor selectivity; 5-hydroxytryptamine 5-HT3 receptor;guinea-pig intestine; rat brain; Von Bezold Jarisch reflex

Animals↗
PubMed1996

[3H]-thioperamide as a radioligand for the histamine H3 receptor in rat cerebral cortex.

1. The purpose of the present study was to characterize the binding of the histamine H3 receptor antagonist, [3H]-thioperamide, to rat cerebral cortical membranes. 2. The binding of [3H]-thioperamide to rat cerebral cortical membranes reached equilibrium after incubation with [3H]-thioperamide after 8-10 h at 4 degrees C. Equilibrium was maintained for up to 18 h of incubation. Addition of 1 microM (R)-alpha-methylhistamine rapidly dissociated [3H]-thioperamide from its binding sites. From these kinetic experiments a dissociation constant of 0.3 nM was obtained for [3H]-thioperamide. 3. Saturation experiments with [3H]-thioperamide using 1 microM (R)-alpha-methylhistamine to define nonspecific binding were best analysed according to a single site model. A dissociation constant (KD) of 0.80 +/- 0.06 nM (n = 3) and a maximal number of binding sites (Bmax) of 73 +/- 20 fmol mg-1 protein (n = 3) were obtained for the binding of [3H]-thioperamide to rat cerebral cortical membranes. 4. Saturation experiments with [3H]-thioperamide using 0.3 microM iodophenpropit to define nonspecific binding were best analysed according to a two site model. For the high affinity [3H]-thioperamide site a KD value of 1.1 +/- 0.3 nM (n = 3) and Bmax value of 162 +/- 108 fmol mg-1 protein (n = 3) were obtained whereas KD and Bmax values for the low affinity site were 96 +/- 19 nM and 4346 +/- 3092 fmol mg-1 protein (n = 3), respectively. 5. Using 5 nM [3H]-thioperamide, the binding was hardly displaced by H3 agonists within concentration-ranges expected to bind to the histamine H3 receptor. Under these conditions, [3H]-thioperamide binding was fully displaced by various H3-antagonists, yet most H3 antagonists showed Ki values different from those expected for the histamine H3 receptor. 6. Using 0.3 nM [3H]-thioperamide, 50-60% of the total binding was potently displaced by the H3 agonists histamine, (R)-alpha-methylhistamine, (S)-alpha-methylhistamine, imetit and immepip. Displacement of the binding of 0.3 nM [3H]-thioperamide binding exhibited clear stereoselectivity for the R and S isomers of alpha-methylhistamine. 7. Binding of 0.3 nM [3H]-thioperamide was completely displaced by several H3 antagonists (thioperamide, iodophenpropit, iodoproxyfan, and burimamide) and biphasic displacement curves were obtained; the Ki values for the high affinity site corresponded well with the expected values for the H3 receptor. Antagonists fully displaced the binding of 5 nM [3H]-thioperamide with affinities comparable to the low affinity site found with 0.3 nM [3H]-thioperamide. 8. Ondansetron and haloperidol did not displace binding of 5 nM [3H]-thioperamide at concentrations at which the former are known to bind to 5-HT3 or sigma receptors, respectively. On the other hand, nonselective cytochrome P450 inhibitors displaced the binding of 5 nM [3H]-thioperamide from both rat cerebral cortical membranes and rat liver microsomes. 9. It is concluded that the histamine H3 antagonist, [3H]-thioperamide, can be used as a radioligand to study the histamine H3 receptor in rat brain, provided that subnanomolar concentrations are used in displacement studies. Moreover, the specific binding should be defined with an H3 agonist, since most H3 antagonists share with [3H]-thioperamide a low affinity, high density, non-H3 receptor binding site(s) in rat brain. The latter is probably due to binding to cytochrome P450 isoenzymes.

Animals↗
PubMed1996

Effects of S-ethylisothiourea, a potent inhibitor of nitric oxide synthase, alone or in combination with a nitric oxide donor in splanchnic artery occlusion shock.

1. The aim of this study was to compare the effects of an intravenous infusion of a potent and non selective nitric oxide synthase inhibitor S-ethylisothiourea (Ethyl-TU) with that of a nitric oxide (NO) donor on the pathological sequelae associated with splanchnic artery occlusion (SAO) shock. In addition the effects of the combination of these two treatments were also investigated. 2. SAO shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to evaluate neutrophil accumulation) and the responsiveness of aortic rings to acetylcholine (ACh, 10 nM-10 microM) and to phenylephrine (PE, 1 nM-10 microM) were studied. 3. SAO shocked rats had a decreased survival rate (0% survival 2 h after the release of occlusion) and survival time (76 +/- 10 min), increased MPO activity in the ileum (3.39 +/- 0.8 u x 10(-3) g-1 tissue), a marked leukopenia and a profound hypotension. In addition aortic rings from shocked rats showed a marked hyporeactivity to PE and reduced responsiveness to ACh. Endothelium denuded aortic rings had also a marked hyporeactivity to PE. 4. In vivo administration of Ethyl-TU (0.1 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) significantly increased survival time and rate, improved mean arterial blood pressure, restored the responsiveness to PE, but did not change MPO activity, leukopenia or the impairment in the responsiveness of aortic rings to ACh. Addition of Ethyl-TU (2 microM) to endothelium denuded aortic rings in vitro, restored the marked hyporeactivity to PE. Administration of the NO donor C87-3754 (0.75 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) slightly increased survival time and reduced MPO activity and leukopenia, but did not change survival rate and mean arterial blood pressure. In addition C87-3754 restored the responsiveness of aortic rings to ACh to control values, but did not modify the hyporeactivity to PE. The combination of these two interventions produced a higher degree of protection than either Ethyl-TU or C87-3754 alone. In fact, co-administration of Ethyl-TU plus C87-3754 completely prevented mortality, reduced MPO activity, attenuated leukopenia and the profound hypotension and restored the impaired responsiveness of aortic rings to PE and ACh. 5. Our study suggests that treatment with a nitric oxide synthase inhibitor combined with an NO donor may be a new therapeutic approach to the treatment of splanchnic artery occlusion shock.

Acetylcholine↗
PubMed1984

Occupational dermatoses at a film laboratory.

During the period January 1980-June 1981, an investigation was made of skin diseases among employees of a film laboratory. The investigation was carried out in 5 stages. (I) Questionnaire (II) Clinical examination and interview with all employees who stated that they had had skin disease at some time (III) Patch testing at the laboratory of all cases of suspected occupational dermatoses, and control tests in hospital of 200 non-exposed eczema patients (IV) Investigation of protective gloves by patch testing and in a chemical bath (V) Allergy test on guinea pigs (GPMT) of one agent (PBA-1). The firm had 114 employees and the questionnaire was answered by 103. Altogether 43 persons at some time had been exposed to chemicals in their work, and 21 of them had had occupational dermatoses. In 12 cases, contact allergy was found to one or more of the photographic chemicals CD-2, CD-3, Metol and PBA-1. GPMT with PBA-1 showed it to be a potent sensitizer. The colour developing agents may also give rise to lichenoid reactions and 2 such cases were seen in this investigation. Other causes of occupational dermatoses are indicated, as well as the occurrence of non-occupational skin diseases.

Aminophenols↗