bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory Effect Of Reactive Oxygen Species On Angiotensin I‐Converting Enzyme (Kininase II)
Authors: Michel B , Grima M , Nirina Lb , Ingert C , Coquard C , Barthelmebs M , Imbs Jl 
Published: March 2003

SUMMARY1. Somatic angiotensin I‐converting enzyme (ACE) is a protein that contains two similar domains (N‐ and C‐terminal), each possessing an active site. We have examined the effects of a generator of hydroxyl radicals (g•OH: 2,2′‐azo‐bis(2‐amidinopropane)) and hydrogen peroxide (H2O2) on ACE using an in vitro approach.2. The generator of hydroxyl radicals inactivated ACE in a time (2–6 h)‐ and concentration (0.3–3 mmol/L)‐dependent manner at 37°C. When ACE was coincubated for 4 h with g•OH (3 mmol/L), its activity decreased by 70%. Addition of dimethylthiourea or mannitol + methionine, two •OH scavengers, resulted in a significant protection of ACE activity. Mercaptoethanol and dithiotreitol, two thiol‐reducing agents, also efficiently protected ACE activity.3. The hydrolysis of two natural and domain‐specific substrates was explored. The hydrolysis of angiotensin I, preferentially cleaved by the C‐domain, was significantly inhibited (57–58%) after 4 h exposure to g•OH (0.3–1 mmol/L). Under the same conditions of exposure, the hydrolysis of N‐acetyl‐Ser‐Asp‐Lys‐Pro, a specific substrate for the N‐domain, was only slightly inhibited by 1 mmol/L g•OH.4. Hydrogen peroxide, another source of •OH, was used. After exposure to H2O2 (3 mmol/L; 4 h), an 89% decrease in ACE activity was observed. Pretreatment with the iron chelator deferoxamine (1 mmol/L) attenuated H2O2‐mediated ACE inactivation, demonstrating that the effect of H2O2 was partly due to its conversion into •OH (Fenton reaction).5. In summary, our findings demonstrate that g•OH and H2O2 inhibit ACE activity and suggest a preferential action of g•OH on the C‐domain of the enzyme.
Annual Scientific Meeting of ASCEPT, 1999 Careful Screening To Target Interventions To Prevent Sudden Cardiac Death
Authors: Struthers Allan D 
Published: March 2003

SUMMARY1. Cardiac death is due not only to coronary artery disease, but also to left ventricular (LV) abnormalities (fibrosis, dysfunction) and arrhythmogenic triggers, such as autonomic imbalance.2. Nitric oxide deficiency could be a key mediator leading not only to coronary atherosclerosis, but also to LV abnormalities and autonomic imbalance.3. It may be possible to screen for the above abnormalities (e.g. echocardiography and brain natriuretic peptide levels for LV abnormalities, 24 h tapes for autonomic imbalance and QT interval analysis).4. Once individuals are identified as being at high risk, a range of interventions is possible (e.g. intensive statin therapy or angiotensin‐converting enzyme inhibitors if LV abnormalities or autonomic imbalance are found).
Role Of Protein Kinase C, KATP Channels And Dna Fragmentation In The Infarct Size‐Reducing Effects Of The Free Radical Scavenger T‐0970
Authors: Hashimoto Kazuaki , Minatoguchi Shinya , Hashimoto Yasuko , Wang Ningyuan , Qiu Xinbin , Yamashita Kazuya , Uno Yoshihiro , Arai Masazumi , Nishida Yoshio , Takemura Genzou , Suzuki Toshikazu , Fujiwara Takako , Fujiwara Hisayoshi 
Published: March 2003

SUMMARY1. In the present study, we investigated the effect of 1‐(3‐ tert‐butyl‐2‐hydroxy‐5‐methoxyphenyl)‐3‐(3‐pyridylmethyl) urea hydrocloride (T‐0970), a novel water‐soluble low‐molecular weight free radical scavenger, on the generation of hydroxyl radicals in vivo and on myocardial infarct size in an in vivo model of myocardial infarction in rabbits.2. T‐0970 scavenged hydroxyl radicals generated in the myocardium during reperfusion, as assessed by using a microdialysis technique and HPLC in an in vivo model with 30 min coronary occlusion and 30 min reperfusion in rabbits.3. Another group of rabbits was subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was infused with saline for 190 min from 10 min before occlusion to 180 min after reperfusion. The treatment group (T‐0970 group; n = 10) was injected with a bolus 2.5 mg/kg T‐0970 and then infused with T‐0970 for 190 min from 10 min before reperfusion to 180 min after reperfusion at a rate of 100 μg/kg per min. The T‐0970 + CHE group (n = 5) was given chelerythrine (CHE; a selective inhibitor of protein kinase C (PKC); 5 mg/kg, i.v.) 10 min before the administration of T‐0970. The T‐0970 + 5‐HD group (n = 5) was given 5‐hydroxydecanoate (5‐HD; an inhibitor of mitochondrial KATP channels; 5 mg/kg, i.v.) 10 min before the administration of T‐0970. The CHE and 5‐HD groups were given CHE (5 mg/kg, i.v.) and 5‐HD (5 mg/kg, i.v.) 20 min before reperfusion, respectively. After 48 h reperfusion, infarct size was measured histologically and expressed as a percentage of the area at risk (AAR). In another series of experiments, the control (n = 5) and T‐0970 (n = 5) groups were killed 4 h after reperfusion following 30 min coronary occlusion and DNA fragmentation in myocytes was assessed using in situ dUTP nick end‐labelling (TUNEL) at the light microscopic level.4. Infarct size, as a percentage of AAR, in the T‐0970 group was significantly reduced compared with the control group (21±4 vs 41±4%, respectively; P < 0.05). This reduction of infarct size by T‐0970 was abolished by pretreatment with CHE and 5‐HD. Neither CHE nor 5‐HD alone had any effect on infarct size. The percentage of infarcted myocytes with DNA fragmentation by TUNEL in the T‐0970 group was significantly reduced compared with the number in the control group (4.0±1.5 vs 10.7±1.9%, respectively; P < 0.05).5. T‐0970, a free radical scavenger, improved reperfusion injury. This effect seemed to be mediated by activation of PKC, the opening of mitochondrial KATP channels and inhibition of DNA fragmentation.
Role Of Nitric Oxide On Pressor Mechanisms Within The Dorsomedial And Rostral Ventrolateral Medulla In Anaesthetized Cats
Authors: Chen Shu‐Ying , Mao Shih‐Peng , Chai Chok‐Yung 
Published: March 2003

SUMMARY1. The role of nitric oxide (NO) in central cardiovascular regulation and the correlation between NO and glutamate‐induced mechanisms is not clear. Microinjection of glutamate (3 nmol/ 30 nL) into dorsomedial medulla (DM) and rostral ventrolateral medulla (RVLM) increased arterial blood pressure (BP) and sympathetic vertebral nerve activity (VNA). Thus, in the present study, we examined the modulation by NO of glutamate‐induced pressor responses in the DM and RVLM of cats.2. Histochemical methods using nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) as a marker to stain neurons containing NO synthase (NOS), showed positive findings of NOS in both the DM and RVLM.3. Microinjection of NG‐nitro‐L‐arginine methyl ester (L‐NAME), a NOS inhibitor, into the DM or RVLM did not alter resting BP and VNA, but it did cause a dose‐dependent attenuation of glutamate‐induced pressor responses. Interestingly, the increase in NO levels that resulted from pretreatment with L‐arginine (L‐Arg) or sodium nitroprusside (SNP) did not alter resting BP and VNA, but still inhibited glutamate‐induced pressor responses in the DM and RVLM in a dose‐dependent manner.4. We also examined whether NO modulated the pressor responses induced by activation of different excitatory amino acid receptors. N‐Methyl‐D‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole proprionic acid (AMPA) were used. Consistent with the results from the initial glutamate studies, we observed that not only L‐NAME, but also L‐Arg and SNP attenuated pressor responses induced by NMDA and AMPA. No difference was found between the effects of NO on NMDA‐ and AMPA‐induced pressor responses.5. To investigate the possibility of a loss of agonist selectivity, the effects of D‐2‐amino‐5‐phosphonovalerate (D‐AP5) and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) on AMPA and NMDA responses in the DM were examined. The results showed that CNQX did not alter NMDA‐induced pressor responses, while D‐AP5 failed to alter AMPA‐induced responses.6. Our results suggest that activation of the glutamate‐induced pressor mechanism is regulated by changes in NO levels in the DM and RVLM. This implies that NO may play a permissive role to allow operation of the glutamate‐activation mechanism.
Effect of 9‐(6,7‐Dideoxy‐β‐D‐Allo‐Hept‐5‐Ynofuranosyl)Adenine On Noradrenaline Release From Vascular Sympathetic Nerves
Authors: Shinozuka Kazumasa , Ishii‐Nozawa Reiko , Takeuchi Koichi , Minakawa Noriaki , Matsuda Akira , Nakata Hiroyasu , Kunitomo Masaru 
Published: March 2003

SUMMARY1. The effects of 9‐(6,7‐dideoxy‐β‐D‐allo‐hept‐5‐ynofuranosyl)adenine (HAK2701), a selective and potent ligand for P3 receptor‐like protein, on the release of endogenous noradrenaline (NA) from electrically stimulated rat mesenteric artery and rabbit ear artery were compared with those of a number of purinoceptor agonists.2. In the rat mesenteric artery, the P1 receptor agonists 2‐chloroadenosine (2CA) and 5′‐N‐ethylcarboxamidoadenosine (NECA) and the P2 purinoceptor agonists β,γ‐methylene ATP (βγmATP) and 2‐methylthio ATP (2mSATP) significantly inhibited the release of NA in a xanthine‐sensitive manner. HAK2701 did not significantly inhibit the release of NA, the relative order of potency being βγmATP > NECA > 2CA > 2mSATP >> HAK2701.3. In the rabbit ear artery, both P1 and P2 receptor agonists significantly facilitated the release of NA in a xanthine‐sensitive manner. HAK2701 also significantly facilitated the release of NA, the relative order of potency being HAK2701 > βγmATP > 2CA > 2mSATP > NECA.4. These findings suggest that HAK2701 may be a potent and selective agonist for facilitatory prejunctional purinoceptors, but not for inhibitory purinoceptors, on adrenergic nerve terminals.
Extracellular ATP and cAMP as Paracrine and Interorgan Regulators of Renal Function ATP Release Mechanisms, ATP Receptors and Purinergic Signalling along the Nephron
Authors: Schwiebert Erik M 
Published: March 2003

SUMMARY1. Autocrine and paracrine signalling along the nephron of the kidney has been a widely held hypothesis for several decades. The lumen of the nephron is an ideal autocrine and paracrine signalling microenvironment. Any agonist, filtered at the glomerulus or released in the proximal tubule or other proximal segments, is subsequently trapped in the lumen of the nephron and present to interact with luminal receptors. Similar signalling in the renal interstitium is also possible and likely. Indeed, receptors for many autocrine and paracrine agonists have been characterized on the luminal membrane and serosal membrane of multiple nephron segments.2. An important family of autocrine and paracrine agonists in the kidney are the purinergic agonists. Extracellular ATP, as well as its metabolites (ADP, 5′‐AMP and adenosine), is released by renal epithelial cells. These compounds are also freely filtered at the glomerulus and are found in the final urine. Receptors for ATP and adenosine are also expressed on the luminal and serosal side of many nephron segments.3. The present review discusses purinergic signalling by nucleotide agonists in an integrated manner, from ATP release to ATP receptors to extracellular ATP‐mediated effects on renal epithelial function. These themes are the focus of our laboratory in normal and polycystic kidneys as well as in normal and diseased epithelial cells from other tissues. The physiological roles of extracellular purinergic signalling in the kidney and other tissues are only beginning to emerge.
Effects In Humans Of Intravenously Administered Endotoxin On Soluble Cell‐Adhesion Molecule And Inflammatory Markers: A Model Of Human Diseases
Authors: Wilson Mf , Blum R , Dandona P , Mousa Sa 
Published: March 2003

SUMMARY1. Endotoxin, a component of the cell wall of Gram‐negative bacteria, could be a predisposing mediator of many pathological disorders. The present study was undertaken to determine the effects and time‐course of acute endotoxin challenge on inflammatory and cell‐adhesion molecule markers shedding in the plasma as potential surrogates.2. Six normal male subjects per group (age range 21–35 years) were injected with 4 ng/kg, i.v., reference standard Escherichia coli (0113:h10:k) endotoxin or physiological saline.3. Plasma inflammatory markers (tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and TNF‐receptor I (RI)) and cell‐adhesion molecule markers (soluble L‐selectin, soluble P‐selectin, soluble vascular cell adhesion molecule (VCAM)‐1) were determined using sensitive and specific ELISA.4. Tumour necrosis factor‐α increased from a basal level of 2.8 pg/mL to approximately 800 pg/mL at 90 min after endotoxin. Similarly, IL‐6 peaked 2–3 h after endotoxin injection, with a rapid decline by 6–8 h, and levels returned to basal values by 24 h.5. In contrast, TNF‐RI peaked at 2 h (increasing from basal levels of 900–3300 pg/mL) with a much slower decline and without return to basal levels at 24 h (1400 pg/mL).6. Endotoxin resulted in a rapid rise in soluble L‐selectin within 1 h, which increased from a basal of 150–425 ng/mL. This rapid rise in soluble L‐selectin was sustained for up to 2.5 h and then rapidly declined to basal levels by 3.5 h.7. In contrast, plasma soluble P‐selectin levels showed a delayed and progressive increase up to 8 h (increasing from a basal level of 50–95 ng/mL), with a partial decline at 24 h (80 ng/mL).8. Similarly, soluble VCAM‐1 levels showed a progressive rise up to 24 h (increasing from basal values of 600–1000 ng/mL).9. This acute human model of endotoxin exposure demonstrated an upregulation of inflammatory stimuli leading to a short‐term hyperactivation of leucocytes and a more sustained activation of platelets and endothelium.10. This model provides a non‐invasive method for studying the complex effects of endotoxin‐like pathogens on different cellular events using soluble plasma surrogate markers.
Non‐Invasive Single Cell pH Measurements In The Isolated Perfused Pancreas
Authors: Mooren Frank C , Domschke Wolfram , Kinne Rolf Kh , Gronczewski Jacek , Lerch Markus M 
Published: March 2003

SUMMARY1. A new method was developed for non‐invasive investigations of intracellular pH (pHi) regulation in different cell types of the isolated perfused pancreas using a confocal laser scanning technique.2. After removal of the rat pancreas the coeliac artery was cannulated and the splenic segment of the pancreas was perfused with dextran (5%)–Ringer solution at a constant flow rate of 2 mL/min. In a temperature‐controlled (37°C) chamber, pH regulation was studied using the pH‐sensitive fluorescent dye 2′,7′‐bis‐(2‐carboxyethyl)‐5‐(‐6)‐carboxyfluorescein (BCECF) with a confocal microscope (MRC‐600; Bio‐Rad, Hercules, CA, USA).3. Image analysis permitted the identification and comparison of different cell types with a pHi of 7.26±0.1 in acinar cells and of 7.02±0.1 in endothelial cells. Increasing PCO2 from 5 to 20% resulted in a rapid decrease in pHi. Omission of sodium from the perfusate resulted in a smooth decline in pHi. Both decreases were found to be fully reversible. Increasing PCO2 under sodium‐free conditions also resulted in a drop of pHi that was, however, not fully reversible, suggesting involvement of the Na+/H+ exchanger in the regulation of pHi in the intact organ.4. The above method completely preserves tissue integrity and, therefore, allows the study of pH regulation in different cell types of the pancreas simultaneously and without interference with their functional arrangement. The technique should be of specific value to investigate experimental disease states of the pancreas.
Fibroblast Growth Factors In The Developing Central Nervous System
Authors: Ford‐Perriss Miriam , Abud Helen , Murphy Mark 
Published: March 2003

SUMMARY1. It is now clear that members of the fibroblast growth factor (FGF) family have multiple roles during the formation of the central nervous system (CNS).2. There are at least 23 members of the FGF family and, of these, 10 are expressed in the developing CNS, along with four FGF receptors (FGFR‐1–4).3. The present review discusses the roles of these FGFs, with emphasis on FGF‐2, FGF‐8, FGF‐15 and FGF‐17. Fibroblast growth factors‐2 and ‐15 are generally expressed throughout the developing CNS, whereas FGF‐8 and FGF‐17 are tightly localized to specific regions of the developing brain and are only expressed in the embryo during the early phases of proliferation and neurogenesis.4. Expression studies on FGFRs in the chick and mouse indicate that FGFR‐1 is most generally expressed, whereas FGFR‐2 and FGFR‐3 show highly localized but changing patterns of expression throughout CNS development. The FGFR‐4 has been localized to the developing CNS in fish but not at a detailed level, as yet, in chick or mouse.5. A picture is emerging from these studies that particular FGFs signal through specific receptors in a highly localized manner to regulate the development of different regions of the brain.6. This picture has been demonstrated so far for the developing cortex (FGF‐2–/– mice), the forebrain and midbrain (FGF‐8 hypomorphs) and the cerebellum (FGF‐17/FGF‐8 mutant mice). In addition, generation of mutant animals deleted for FGFR‐1 and FGFR‐2b IIIb demonstrate their importance in FGF signalling.7. However, there are significant gaps in our knowledge of the localization of members of the FGF family and their receptors. More detailed information on the spatio‐temporal mapping of FGFs and FGFR isoforms is required in order to understand the molecular mechanisms through which FGFs signal.
Airway Protection Following Simulated Gastro‐Oesophageal Reflux In Sedated And Sleeping Neonatal Piglets During Active Sleep
Authors: McKelvey George M , Post Elizabeth J , Wood Andrew Kw , Jeffery Heather E 
Published: March 2003

SUMMARY1. In infants, promethazine has been implicated in the pathogenesis of sleep apnoea, apparent life threatening events (ALTE) and the Sudden Infant Death syndrome (SIDS). The aim of the present study was to investigate, in a neonatal animal, the effects of a commonly used promethazine‐containing medication on airway protective mechanisms and cardiorespiratory reflexes following simulated gastro‐oesophageal reflux (GER) to different levels in the oesophagus and pharynx.2. Physiological and radiographic recordings were made in 21 naturally sleeping (controls) and 21 sedated (1.5 mg/kg, p.o., promethazine) piglets. On 3 consecutive days physiological recordings were made in all piglets during active sleep. Gastro‐oesophageal reflux was simulated by the injection of boluses of 0.5 mL HCl, pH 2 or 3, or NaCl (0.9%) at 37°C into the pharynx, upper or lower oesophagus.3. In healthy neonatal piglets, minimal sedation with promethazine, which did not affect behaviour during wakefulness, revealed previously unreported findings during active sleep.4. The most significant effects were observed following simulated GER to the pharynx, with no effect observed in the lower oesophagus. In sedated piglets, compared with naturally sleeping piglets, there was a significant reduction in swallowing (P < 0.01), delayed radiological clearance of fluid (P < 0.05), a reduction in breathing rate, oxygen saturation and heart rate and an increase in apnoea.5. These findings are consistent with a low dose of promethazine producing a significant attenuation of airway protective mechanisms and, thus, stimulation of the laryngeal chemoreflex. The results suggest a mechanism for the association observed between promethazine use and the occurrence of ALTE and SIDS. The results support continued caution and suggest the need for greater regulation of promethazine‐containing medications in infants.
Circumventricular Organs: Gateways to the BrainMultisynaptic Neuronal Pathways From The Submandibular And Sublingual Glands To The Lamina Terminalis In The Rat: A Model For The Role Of The Lamina Terminalis In The Control Of Osmo‐ And Thermoregulatory Behaviour
Authors: Hübschle Thomas , Mathai Michael L , McKinley Michael J , Oldfield Brian J 
Published: March 2003

SUMMARY1. The putative regulatory role of the lamina terminalis in the central control of salivation was investigated in the rat using the viral‐tracing technique and Fos‐immunohistochemistry.2. Neurons situated in the lamina terminalis, such as the vascular organ of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO), were retrogradely labelled after pseudorabies virus injections into the submandibular or sublingual gland.3. Viral tracing combined with glandular denervation showed that lamina terminalis structures sent efferents, in particular, to the parasympathetic side of submandibular gland innervation.4. Saliva lost under heat stress has severe implications for the body fluid economy of rats and a key to the understanding of the central regulation of heat‐induced salivation may be the integrative role of the lamina terminalis processing thermoregulatory and osmoregulatory information.
Effects of adenosine administration on spike‐wave discharge frequency in genetically epileptic rats
Authors: Ilbay Gul , Sahin Deniz , Karson Ayse , Ates Nurbay 
Published: March 2003

SUMMARY1. In the present study, the effects of the administration of adenosine on absence seizures were investigated in the Wistar Albino Glaxo/Rijswijk (WAG/Rij) strain of rats, which are an adequate model for human absence epilepsy.2. After baseline electroencephalogram (EEG) recording, adenosine was injected intraperitonealy (i.p.) at doses of 6, 30 and 120 mg/kg and EEG recordings were continued for 1 h postinjection. In addition, to enable evaluation of the contribution of peripheral factors to the occurrence of spike‐wave discharges (SWD) after adenosine injection, arterial blood pressure and rectal temperature were also recorded.3. Injection of adenosine induced a dose‐dependent increase in the appearance of SWD. The number and total duration of SWD were found to be significantly increased after 30 and 120 mg/kg adenosine (P < 0.05). Adenosine also induced a fall in both blood pressure and body temperature in all experimental groups.4. These results show that peripheral administration of adenosine promotes absence seizures. It is likely that the lowering of blood pressure and body temperature and the activation of sensory afferents after adenosine injection may contribute to the facilitation of SWD observed in the present study.
Protein Kinase C and Changes In Manganese Superoxide Dismutase Gene Expression In Cultured Glial Cells
Authors: Huang Wei‐Chien , Chen Pei‐Chi , Jou Shou‐Bin , Cheng Juei‐Tang 
Published: March 2003

SUMMARY1. To study the role of protein kinase C (PKC) in the increase in manganese superoxide dismutase (Mn‐SOD) gene expression following transient hypoxia in glial cells, we examined the mRNA levels of Mn‐SOD using northern blot analysis.2. The Mn‐SOD mRNA levels were markedly increased after exposure to nitrogen gas for 5 min.3. Pretreatment with chelerythrine or GF109203x, inhibitors of PKC, attenuated the increase in Mn‐SOD mRNA following hypoxia in a concentration‐dependent manner.4. Incubation with phorbol 12‐myristate 13‐acetate, the PKC activator, enhanced the increase in Mn‐SOD gene expression in response to transient hypoxia.5. The results suggest that hypoxia increases Mn‐SOD gene expression in cultured glial cells mainly through activation of a PKC pathway.