Abstract:
:1. Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide with superoxide anion, and hydroxyl radical, formed in the iron-catalysed Fenton reaction, are important mediators of reperfusion injury. In in vitro studies, DNA single strand breakage, triggered by peroxynitrite or by hydroxyl radical, activates the nuclear enzyme poly (ADP-ribose) synthetase (PARS), with consequent cytotoxic effects. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of splanchnic artery occlusion shock. 2. Splanchnic artery occlusion and reperfusion shock (SAO/R) was induced in rats by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. 3. SAO/R rats developed a significant fall in mean arterial blood pressure, significant increase of tissue myeloperoxidase activity and marked histological injury to the distal ileum. SAO/R was also associated with a significant mortality (0% survival at 2 h after reperfusion). 4. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO/R rats, starting early after reperfusion, but not during ischaemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific 'footprint' of peroxynitrite, in the necrotic ileum in shocked rats, as measured at 60 min after the start of reperfusion. 5. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). 6. In a separate set of studies, using a 4000 Dalton fluorescent dextran tracer, we investigated the changes in epithelial permeability associated with SAO/R. Ten minutes of reperfusion, after 30 min of splanchnic artery ischaemia, resulted in a marked increase in epithelial permeability. 7. There was a significant increase in PARS activity in the intestinal epithelial cells, as measured 10 min after reperfusion ex vivo. 3-Aminobenzamide, a pharmacological inhibitor of PARS (applied at 10 mg kg(-1), i.v., 5 min before reperfusion, followed by an infusion of 10 mg kg(-1) h(-1)), significantly reduced ischaemia/reperfusion injury in the bowel, as evaluated by histological examination. Also it significantly improved mean arterial blood pressure, improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and reduced the reperfusion-induced increase in epithelial permeability. 8. 3-Aminobenzamide also prevented the infiltration of neutrophils into the reperfused intestine, as evidenced by reduced myeloperoxidase activity. It improved the histological status of the reperfused tissues, reduced the production of peroxynitrite in the late phase of reperfusion and improved survival. 9. In conclusion, our study demonstrates that the PARS inhibitor 3-aminobenzamide exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock. We suggest that peroxynitrite and/or hydroxyl radical, produced during the reperfusion phase, trigger DNA strand breakage, PARS activation and subsequent cellular dysfunction. The vascular endothelium is likely to represent an important cellular site of protection by 3-aminobenzamide in SAO shock.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Cuzzocrea S,Zingarelli B,Costantino G,Szabó A,Salzman AL,Caputi AP,Szabó Cdoi
10.1038/sj.bjp.0701234subject
Has Abstractpub_date
1997-07-01 00:00:00pages
1065-74issue
6eissn
0007-1188issn
1476-5381journal_volume
121pub_type
杂志文章abstract::1. Diabetic modifications of nicotinic receptor-operated noncontractile Ca2- mobilization observed in the presence of anticholinesterase were investigated by measuring Ca(2+)-aequorin luminescence in diaphragm muscles of mice with diabetes induced by injections of streptozotocin (150 mg kg-1, bolus i.v.) and alloxan (...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb17227.x
更新日期:1995-11-01 00:00:00
abstract::The electrically-evoked contractions of the rat vas deferens were selectively inhibited by beta-endorphin, the preparation being much less sensitive to enkephalins and narcotic analgesic drugs. However, introduction of D-Ala in position 2 of [Leu]-enkephalin enhanced the activity of the opioid peptide to the order of ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1978.tb08653.x
更新日期:1978-11-01 00:00:00
abstract::1. The effects of a series of nine GABAB receptor antagonists of widely varying potencies on electrically stimulated release from cortical slices of [3H]-GABA in the absence or presence of 10 microM of the GABAB agonist, (-)-baclofen and of endogenous glutamate in the presence of (-)-baclofen were compared. 2. The con...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17168.x
更新日期:1994-12-01 00:00:00
abstract::Irritable bowel syndrome is characterized by visceral hyperalgesia commonly associated with stress and inflammatory processes. We investigated the role of tachykinin NK2 receptors in the ability of trinitrobenzenesulphonic acid (TNBS) and stress to enhance the sensitivity of the rat rectum to distension using a select...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703040
更新日期:2000-01-01 00:00:00
abstract::1. Selective antagonism of the cardiac beta(1)-adrenoceptors has been studied in normal human volunteers.2. Practolol and UK 6558 produced greater antagonism of the chronotropic and inotropic responses to i.v. isoprenaline than of the vasodilator response to either i.v. or intra-arterial isoprenaline. A third drug, M&...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08272.x
更新日期:1973-09-01 00:00:00
abstract::1 The beta-adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea-pig liver slices, in contrast to the large hyperpolarizations seen with alpha-agonists. However, after a selective alpha-adrenoceptor agonist has been applied, the response t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb06991.x
更新日期:1977-01-01 00:00:00
abstract::1. Reserpine given to rats before the enhanced synthesis of DNA begins 14h after partial hepatectomy markedly depresses thymidine uptake into DNA at 24 hours.2. At this time decreased activity of liver thymidine kinase but unchanged thymidine 5'-nucleotidase were observed.3. Reserpine has no effect on DNA synthesis wh...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08370.x
更新日期:1973-10-01 00:00:00
abstract::1. To characterize the muscarinic receptors on human pulmonary veins associated with the acetylcholine (ACh)-induced relaxation, isolated venous and arterial preparations were pre-contracted with noradrenaline (10 microM) and were subsequently challenged with ACh in the absence or presence of selective muscarinic anta...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703301
更新日期:2000-05-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00830.x
更新日期:2010-08-01 00:00:00
abstract::1 The ability of drugs to inhibit noradrenaline accumulation and to release noradrenaline was studied in the isolated anococcygeus muscle of the rat. 2 Noradrenaline, tyramine, 2-amino,6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), 2-amino,6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (dimethyl ADTN), and 5-hydroxy...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1978.tb07798.x
更新日期:1978-07-01 00:00:00
abstract::Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, su...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0706328
更新日期:2005-09-01 00:00:00
abstract::Expression of two isoforms of Rho-kinase (ROCK) and its functional role in the physiological control of smooth muscle contraction in the sheep ureter were investigated. Helical strips of the ureteric smooth muscle were stimulated by electrical field stimulation (EFS, 60 V, 1 mS, 2, 4, 8, 16 and 32 Hz, for 20 S), KCl (...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705961
更新日期:2004-10-01 00:00:00
abstract::1. Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible roles in various pathologies, including cytoprotection. Although the exact function of sigma-1 (sigma(1)) receptors is not yet known, their role in the regulation of intracellular Ca(2+) levels and sterol biosynthesis, fu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704626
更新日期:2002-04-01 00:00:00
abstract::1. Measurements were made of the uptake, metabolism and release of [(3)H]-adrenaline by human platelets in citrated plasma or in an artificial medium.2. Radioactive adrenaline was not taken up at 0-2 degrees C. At 37 degrees C there was a slow uptake which continued for at least 5 hours.3. About half of the radioactiv...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb09903.x
更新日期:1970-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Emerging evidence indicates that hypertension is mediated by immune mechanisms. We hypothesized that exposure to Porphyromonas gingivalis antigens, commonly encountered in periodontal disease, can enhance immune activation in hypertension and exacerbate the elevation in BP, vascular inflammation ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14536
更新日期:2019-06-01 00:00:00
abstract::The effects of aconitine, an Aconitum alkaloid, on spontaneous inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs respectively) were investigated in the mechanically dissociated rat ventromedial hypothalamic (VMH) neurons in which native presynaptic nerve terminals remained intact. Under current-clamp co...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704517
更新日期:2002-02-01 00:00:00
abstract::Intraperitoneal and intracerebral injections of methyl beta-carboline-3-carboxylate (beta CCM) and intracerebral injections of RO 15-1788 were given to rats. The performance of the rats in the social interaction test was measured to determine if changes in social interaction induced by beta CCM were mediated in part b...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb08955.x
更新日期:1985-11-01 00:00:00
abstract::1. The aim of the present experiments was to investigate the pharmacological action of a toxin from the spider Phoneutria nigriventer, Tx3-3, on the function of calcium channels that control exocytosis of synaptic vesicles. 2. Tx3-3, in confirmation of previous work, diminished the intracellular calcium increase induc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701381
更新日期:1997-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti-cancer agents. However, new-onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms asso...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01716.x
更新日期:2012-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Lung cancer is one of the leading causes of cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis. EXPERIMENTA...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13176
更新日期:2015-08-01 00:00:00
abstract::1. We have investigated the effects of the selective phosphodiesterase (PDE) type 4 inhibitor, rolipram (0.01-1 microM) on cytosolic Ca2+ fluxes in FMLP-activated human neutrophils, as well as on superoxide production by, and release of elastase from, these cells. 2. Cytosolic Ca2+ fluxes were measured by use of fura-...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701849
更新日期:1998-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. E...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13271
更新日期:2015-11-01 00:00:00
abstract::1. The effect of in vivo desensitization to leukotriene B4 (LTB4) on eosinophil infiltration in response to recombinant C5a was examined in guinea-pig skin. 2. LTB4 (10-300 ng) and C5a (1-10 micrograms) caused a dose-dependent increase in the levels of eosinophil peroxidase activity (a measure of eosinophil infiltrati...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb16182.x
更新日期:1994-09-01 00:00:00
abstract::1. The binding of 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]-DPCPX), an antagonist radioligand selective for adenosine A1 receptors, was studied in rat duodenum, colon muscularis mucosae and longitudinal muscle, urinary bladder and vasa deferentia. 2. [3H]-DPCPX bound with high affinity to a single site in all memb...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17132.x
更新日期:1994-12-01 00:00:00
abstract::1. The effects of capsaicin on voltage-gated Ca2+ currents (ICa), and intracellular Ca2+ concentrations [( Ca2+]i) in cultured dorsal root ganglion (DRG) neurones of the rat were examined in vitro by use of combined patch clamp-microfluorometric recordings. 2. Under voltage-clamp conditions, capsaicin (0.1-10 microM) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb12725.x
更新日期:1990-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), formed nitric oxide (NO)-dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8-nitro-cGMP in diabetic mice, we compare...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01201.x
更新日期:2011-04-01 00:00:00
abstract::1. 5-Hydroxytryptamine (5-HT) transport has been investigated in rat blood platelets poisoned with dinitrophenol-sodium fluoride or ouabain.2. The inhibition of transport produced by different concentrations of the metabolic inhibitors has been correlated with changes in the internal Na(+) and K(+) concentrations of t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb07220.x
更新日期:1971-12-01 00:00:00
abstract::Anthracyclines can cause cumulative dose-related cardiotoxicity characterized by changes in Ca(2+) metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca(2+)-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703538
更新日期:2000-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Neuropeptides are involved in the regulation of food intake in the central nervous system, but they might also act on peripheral fat tissue via neuropeptide receptors. EXPERIMENTAL APPROACH:We investigated the receptor expression and activity of pituitary adenylate cyclase-activating polypeptide...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00164.x
更新日期:2009-06-01 00:00:00
abstract::1. The effects of a new kind of volatile anaesthetic, sevoflurane (Sev), on gamma-aminobutyric acid (GABA)-gated chloride current (Icl) in single neurones dissociated from the rat hippocampal CA1 area were examined using the nystatin perforated patch recording configuration under the voltage-clamp condition. All drugs...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15772.x
更新日期:1996-11-01 00:00:00