bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition Of Transcription Factors By Anti‐Inflammatory And Anti‐Rheumatic Drugs: Can Variability In Response Be Overcome?
Authors: Handel Malcolm L , Nguyen Ly Qq , Lehmann Thomas P 
Published: March 2003

SUMMARY1. The drugs used in the treatment of rheumatoid arthritis (RA) form a diverse group with unpredictable adverse effects, mostly weak efficacy and variable responses. Despite their differences, a common feature of many anti‐inflammatory and disease‐modifying anti‐rheumatic drugs (DMARD) is inhibition of pro‐inflammatory transcription factors, particularly nuclear factor (NF)‐κB and activator protein (AP)‐1.2. The present brief review identifies those drugs capable of inhibiting transcription factors, particularly steroids, gold salts, D‐penicillamine, cyclosporine A and possibly salicylates.3. The newer biological inhibitors of tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β are capable of indirect inhibition of NF‐κB activation, although even with these potent agents the problem of variability in response has not disappeared.4. The development of selective inhibitors of the transcription factor NF‐κB should have the benefit of the anti‐inflammatory drugs and DMARD, both new and old.5. It is hypothesized that this strategy will overcome much of the variability in the therapeutic response and adverse effects that limit the usefulness of the exisiting drugs in the treatment of RA.
Importance Of Histamine, Glutathione And Oxyradicals In Modulating Gastric Haemorrhagic Ulcer In Septic Rats
Authors: Hung Chen‐Road 
Published: March 2003

SUMMARY1. The ulcerogenesis of gastric haemorrhagic damage during sepsis is unclear. The present study first proposes that gastric haemorrhagic ulcer is modulated by mucosal glutathione, histamine and oxyradicals in lipopolysaccharide (LPS)‐induced sepsis in rats. The protective effects of several drugs on the ulcerogenic parameters also were evaluated.2. Male specific pyrogen‐free Wistar rats were deprived of food for 24 h. For the induction of sepsis, intravenous LPS (0, 1, 3 or 10 mg/kg in 1 mL sterilized normal saline) was challenged to rats 12 h after withdrawal of food. Rat stomachs were vagotomized, followed by irrigation for 3 h with normal saline or a physiological acid solution containing 100 mmol/L HCl and 54 mmol/L NaCl.3. The aggravation of gastric ulcerogenic parameters, such as gastric acid back‐diffusion, luminal haemoglobin content, mucosal lipid peroxide production, histamine concentration, as well as lowered concentrations of defensive substances, including mucosal glutathione, were dependent on the doses of LPS used for challenge. A high correlation was observed between mucosal histamine release and lipid peroxide production in LPS rats.4. The ulcerogenic parameters obtained in LPS (3 mg/kg, i.v.) rats were potently attenuated by diamine oxidase, ketotifen and zinc sulphate.5. Several oxyradical scavengers, including glutathione, dimethylsulphoxide and allopurinol, also were effective in inhibiting haemorrhagic ulcer.6. In conclusion, gastric mucosal histamine release and oxyradical generation play pivotal roles in the formation of haemorrhagic ulcers in septic rats.
Effects Of The Na+/H+ Exchange Inhibitor Cariporide (HOE 642) On Cardiac Function And Cardiomyocyte Cell Death In Rat Ischaemic–Reperfused Heart
Authors: Otani Hajime , Uchiyama Takamichi , Yamamura Tadashi , Nakao Yoshihisa , Hattori Reiji , Ninomiya Hideki , Kido Masakuni , Kawaguchi Hideki , Osako Motohiko , Imamura Hiroji 
Published: March 2003

SUMMARY1. Na+/H+ exchange has been implicated in the mechanism of reperfusion injury. We examined the effects of the cardiac‐specific Na+/H+ exchange inhibitor cariporide (HOE 642) on postischaemic recovery of cardiac function and cardiomyocyte cell death (i.e. necrosis and apoptosis).2. Rat isolated and buffer‐perfused hearts were subjected to 25 min normothermic global ischaemia followed by 120 min reperfusion. Cariporide (10 μmol/L) or its vehicle (0.01% dimethylsulphoxide) was administered for 15 min before ischaemia and for the first 30 min after reperfusion.3. Cariporide significantly improved the recovery of isovolumic left ventricular function (heart rate, left ventricular developed pressure and left ventricular end‐diastolic pressure) and coronary flow throughout reperfusion. Creatine kinase release during reperfusion was significantly less in the cariporide‐treated heart. In situ terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL)‐ positive cardiomyocytes were also significantly less in the cariporide‐treated heart after 120 min reperfusion. Electron microscopy showed necrotic changes without typical apoptotic features in cardiomyocytes after reperfusion. Such necrotic changes were mitigated by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyocytes using propidium iodide (PI) and Annexin V revealed that cardiomyocytes in the infarct area were stained with only PI or both PI and Annexin V. Cariporide did not alter the pattern of cardiomyocyte staining with PI and Annexin V, although the number of cardiomyocytes stained with PI or PI plus Annexin V was less than that in vehicle‐treated hearts.4. These results suggest that apoptosis is not a major manifestation of cardiomyocyte cell death in the ischaemic– reperfused myocardium and a cariporide‐sensitive mechanism of reperfusion injury promotes both necrotic and apoptotic processes of cell death.
Growth Hormone Secretagogue Actions On The Pituitary Gland: Multiple Receptors For Multiple Ligands?
Authors: Chen Chen 
Published: March 2003

SUMMARY1. Growth hormone (GH) secretion is thought to occur under the reciprocal regulation of two hypothalamic hormones, namely GH‐releasing hormone (GHRH) and somatostatin (SRIF), through their engagement with specific cell‐surface receptors on the anterior pituitary somatotropes.2. In addition to GHRH and SRIF, synthetic GH‐releasing peptides (GHRP) or GH secretagogue(s) (GHS) regulate GH release through the activation of a novel receptor, the GHS receptor (GHS‐R).3. The cloning of the GHS‐R from human, swine and rat identifies a novel G‐protein‐coupled receptor involved in the control of GH secretion and supports the existence of an undiscovered hormone that may activate this receptor.4. Varieties of intracellular signalling systems are suggested to mediate the action of GHS, which include changes in intracellular free Ca2+ ([Ca2+]i), cAMP, protein kinases A and C, phospholipase C etc.5. With regard to the use of signalling systems by GHS, especially a new form of GHRP or GHRP‐2, a clear species difference has been demonstrated, supporting the possibility of more than one type of GHS‐R.
Effect Of Cold On Fetal Heart Rate And Its Variability
Authors: Yu Ze‐Yan , Lumbers Eugenie R 
Published: March 2003

SUMMARY1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140–144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after β‐adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses).2. Injection of ice‐cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46±1 to 55±1 mmHg (P < 0.001) and HR from 156±2 to 182±2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5±0.2 to 8.0±0.2% (P < 0.001) and total power spectral density (PSD) increased from 78±6 to 278±16 units (P < 0.001) as measured by PSA. Within 100 s, MAP, HR and HRV had returned to baseline.3. β‐Adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold.4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.
Effects Of Dipyridamole And Adenosine On Vasoactive Peptides Calcitonin Gene‐Related Peptide And Atrial Natriuretic Peptide In Humans: Role Of Sympathetic Activation
Authors: Guideri Francesca , Capecchi Pier Leopoldo , Lazzerini Pietro Enea , Pasini Franco Laghi 
Published: March 2003

SUMMARY1. It has been observed that dipyridamole (DIP) administration produces equivalent cardiovascular effects at lower systemic adenosine (ADO) plasma concentrations than those obtained with exogenous ADO infusion. This observation led to the identification of DIP for additional ‘ischaemia‐inducing’ mechanisms, possibly based on sympathetic activation.2. In turn, exogenous ADO administration has proven to elicit a complex neurohumoral response, including an increase in the plasma concentration of catecholamines, associated with augmented levels of the vasoactive peptides calcitonin gene‐related peptide (CGRP) and atrial natriuretic peptide (ANP). More particularly, increases in CGRP seem to be dependent on sympathetic activation, while changes in ANP do not.3. In order to clarify some aspects of the activity of DIP on neurohumoral systems, the effects of administration of DIP and ADO on plasma levels of noradrenaline (NA), CGRP and ANP were studied in healthy volunteers. Haemodynamic parameters were also monitored.4. Infusion of exogenous ADO produced plasma levels of ADO as high as 1893±386 nmol/L, together with a significant increase in plasma levels of CGRP, ANP and NA. Similarly, the infusion of DIP produced augmented plasma concentrations of the examined parameters, with a peak plasma ADO concentration of 470±49 nmol/L.5. At a given ADO plasma concentration of 450±10 nmol/L, the increase in CGRP and NA levels with DIP infusion was significantly higher than that observed following the infusion of ADO, whereas the increase in the plasma concentration of ANP following DIP infusion was very similar to that seen following ADO infusion.6. The physiological background of these findings is based on evidence that DIP displays a greater sympathoexcitatory activity than does exogenous ADO and only the increase in plasma CGRP seems to be mediated, although indirectly, by β‐adrenoceptor stimulation. The exact mechanism of DIP‐dependent sympathetic activation remains to be elucidated.
High Plasma Concentrations Of Prorenin In A Transgenic Animal Model Of Nephropathy With Overexpression Of Transforming Growth Factor‐β1 In The Kidneys
Authors: Krag Søren , Nielsen Arne Høj , Wogensen Lise 
Published: March 2003

SUMMARY1. Plasma concentrations of prorenin were determined in a transgenic animal model of nephropathy induced by overexpression of transforming growth factor (TGF)‐β1 in the juxtaglomerular apparatus.2. In both female and male mice, plasma concentrations of prorenin were higher in transgenic than in non‐transgenic animals. In sexually mature mice, plasma prorenin concentrations were higher in males than in females in both transgenic and non‐transgenic animals in accordance with a sexual dimorphism of the plasma concentration of prorenin.3. The results indicate that TGF‐β1‐like androgens increase prorenin secretion in the kidneys and may explain the increased plasma prorenin concentrations in patients with diabetic nephropathy.
Renal And Cardiovascular Actions Of 20‐Hydroxyeicosatetraenoic Acid And Epoxyeicosatrienoic Acids
Authors: Roman Richard J , Maier Kristopher G , Sun Cheng‐Wen , Harder David R , Alonso‐Galicia Magdalena 
Published: March 2003

SUMMARY1. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP)‐dependent pathways to epoxyeicosatrienoic acids (EET) and 20‐hydroxyeicosatetraenoic acid (20‐HETE) in the kidney and the peripheral vasculature.2. The present short review summarizes the renal and cardiovascular actions of these important mediators.3. Epoxyeicosatrienoic acids are vasodilators produced by the endothelium that hyperpolarize vascular smooth muscle (VSM) cells by opening Ca2+‐activated K+ (KCa) channels. 20‐Hydroxyeicosatetraenoic acid is a vasoconstrictor that inhibits the opening of KCa channels in VSM cells. Cytochrome P450 4A inhibitors block the myogenic response of small arterioles to elevations in transmural pressure and autoregulation of renal and cerebral blood flow in vivo. Cytochrome P450 4A blockers also attenuate the vasoconstrictor response to elevations in tissue PO2, suggesting that this system may serve as a vascular oxygen sensor. Nitric oxide and carbon monoxide inhibit the formation of 20‐HETE and a fall in 20‐HETE levels contributes to the activation of KCa channels in VSM cells and the vasodilator response to these gaseous mediators. 20‐Hydroxyeicosatetraenoic acid also mediates the inhibitory actions of peptide hormones on sodium transport in the kidney and the mitogenic effects of growth factors in VSM and mesangial cells. A deficiency in the renal production of 20‐HETE is associated with the development of hypertension in Dahl salt‐sensitive rats.4. In summary, the available evidence indicates that CYP metabolites of AA play a central role in the regulation of renal, pulmonary and vascular function and that abnormalities in this system may contribute to the pathogenesis of cardiovascular diseases.
Quantitative Trait Loci For Lipid Metabolism In The Study Of Oletf × (Oletf × Fischer 344) Backcross Rats
Authors: Yamasaki Yuki , Watanabe Takeshi K , Okuno Shiro , Ono Toshihide , Oga Keiko , Mizoguchi‐Miyakita Ayako , Goto Yoshihiro , Shinomiya Hiroichi , Momota Hiroshi , Miyao Hideo , Hayashi Isamu , Asai Toshihiro , Suzuki Mikio , Harada Yosuke , Hishigaki Haretsugu , Wakitani Shigeyuki , Takagi Toshihisa , Nakamura Yusuke , Tanigami Akira 
Published: March 2003

SUMMARY1. The Otsuka Long‐Evans Tokushima Fatty (OLETF) rat is a model of type II diabetes with accompanying dyslipidaemia and obesity.2. To define chromosomal intervals associated with obesity (abdominal fat weight and plasma leptin levels), dyslipidaemia (plasma triglyceride, cholesterol and free fatty acids) and hyperglycaemia (plasma glucose levels), we have performed genome‐wide quantitative traits loci (QTL) analyses of 115 male OLETF × (OLETF × Fischer 344) backcross animals at 16 weeks of age.3. The Diabetes Mellitus OLETF type I (Dmo1) locus on rat chromosome 1 showed statistically significant involvement in elevations of plasma levels of triglycerides (P = 4.87 × 10–6 at D1Rat90) and total cholesterol (P = 1.16 × 10–5 at D1Rat306).4. No other loci produced significant linkage to these observed phenotypes.5. These analyses have confirmed the importance of Dmo1 in lipid homeostasis at younger ages as well as during overt diabetes, which appears later. Thus, alterations at the Dmo1 locus are a major risk factor for pathogenesis in the strain, a finding that agrees with physiological studies that indicate a role for dyslipidaemia in the type II diabetic syndrome of OLETF rats.
Role Of Nitric Oxide In Adrenocorticotrophin‐Induced Hypertension: L‐Arginine Effects Reversed By N‐Nitro‐	L‐Arginine
Authors: Wen Cheng , Li Ming , Whitworth Judith A 
Published: March 2003

SUMMARY1. L‐Arginine prevents adrenocorticotrophin (ACTH)‐induced hypertension in the rat. To confirm that this effect is mediated through the nitric oxide (NO) system, we examined whether N‐nitro‐
L‐arginine (NOLA) could reverse the
L‐arginine‐induced blockade of ACTH‐induced hypertension.2. Blood pressure and metabolic parameters were examined in sham‐, ACTH‐, L‐arginine + sham‐, NOLA + sham‐, ACTH +
L‐arginine‐ and ACTH +
L‐arginine + NOLA‐treated Sprague‐Dawley rats (n = 40).3. Adrenocorticotrophin treatment increased systolic blood pressure (SBP), water intake and urine output and decreased bodyweight. N‐Nitro‐
L‐arginine alone increased SBP without affecting metabolic variables.
L‐Arginine alone did not affect blood pressure. The SBP was lower in
L‐arginine + ACTH‐ than ACTH‐treated rats (P < 0.001), but was higher following ACTH +
L‐arginine + NOLA than ACTH +
L‐arginine (P < 0.05).4. N‐Nitro‐
L‐arginine reversed the blood pressure‐lowering effect of
L‐arginine in ACTH‐induced hypertension in the rat, supporting the notion that NO plays a role in the hypertension.
Characterization And Regulation Of Tachykinin Receptors In The Nucleus Tractus Solitarius
Authors: Mazzone Stuart B , Geraghty Dominic P 
Published: March 2003

SUMMARY1. The characteristics, localization and regulation of tachykinin receptors in the rat nucleus tractus solitarius (NTS) involved in respiratory control were investigated using a combination of in vivo microinjection and in vitro autoradiographic techniques.2. Microinjection of receptor‐selective tachykinin agonists and antagonists into the NTS of urethane‐anaesthetized rats suggests that stimulation of NK1 and NK3 receptors increases tidal volume, whereas NK2 and NK3 receptor activation produces a bradypnoea.3. Depletion of NK1 receptors in the NTS due to either ageing or acute hypoxia correlates with a markedly reduced respiratory response to substance P. In contrast, chemical ablation of sensory neurons by neonatal capsaicin administration dramatically increases the respiratory response to a variety of NK1, NK2 and NK3 agonists.4. These studies suggest that all three tachykinin receptors are present in the rat NTS and that these receptors are subject to both acute and chronic regulation.
What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla?
Authors: Dampney RAL , Tagawa T , Horiuchi J , Fontes M , Polson JW 
Published: March 2003

SUMMARY1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla.2. Experimental evidence is reviewed that indicates that these neurons receive both tonic excitatory and tonic inhibitory synaptic inputs. The former appear to be mediated, at least in part, by glutamate receptors and the latter appear to be mediated by GABA receptors.3. There is also evidence that these neurons have the capacity to generate action potentials in the absence of synaptic inputs. However, at present, there is not clear evidence that such an intrinsic pacemaker‐like mechanism contributes to the tonic activity of these neurons under normal resting conditions.4. These neurons are also chemosensitive and this may contribute to their tonic activation under conditions of hypoxia or hypercapnia.
Responses Of Regional Kidney Perfusion To Vasoconstrictors In Anaesthetized Rabbits: Dependence On Agent And Renal Artery Pressure
Authors: Evans Roger G , Correia Anabela G , Weekes Simon R , Madden Anna C 
Published: March 2003

SUMMARY1. We tested the effects of intravenous infusions of angiotensin II (AngII; 300 ng/kg per min) and the vasopressin V1 receptor agonist [Phe
2,Ile
3,Orn
8]‐vasopressin (30 ng/kg per min) on regional kidney perfusion in an extracorporeal circuit model in anaesthetized rabbits in which renal artery pressure (RAP) can be set independently of systemic mean arterial pressure. To test whether the level of RAP can influence the renal vascular response to [Phe
2,Ile
3,Orn
8]‐vasopressin, we compared its effects when RAP was initially set at approximately 65 mmHg with those when RAP was set at approximately 130 mmHg.2. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of AngII increased RAP (13%) and reduced renal blood flow (RBF; 50%) and cortical perfusion (CBF; 43%). Medullary perfusion (MBF) transiently increased during the first 10 min of infusion, but was not significantly different from control levels during the final 5 min of infusion.3. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of [Phe 2,Ile
3,Orn
8]‐vasopressin increased RAP (9%) and reduced RBF (21%); MBF was reduced by 57%, but CBF was reduced by only 15%. In contrast, when RAP was initially set at approximately 130 mmHg, infusion of [Phe
2,Ile
3,Orn
8]‐vasopressin reduced RAP (7%) and increased RBF (13%). In these experiments, MBF was reduced by 38%, but CBF increased by 6%.4. Our experiments show that AngII preferentially reduces CBF, while [Phe 2,Ile
3,Orn
8]‐vasopressin preferentially reduces MBF. The renal vascular responses to [Phe
2,Ile
3,Orn
8]‐ vasopressin appear to be profoundly affected by the level of RAP, because increasing RAP from approximately 65 to approximately 130 mmHg transforms its cortical vasoconstrictor effect into cortical vasodilatation while leaving the response of the medullary microvasculature relatively unchanged. Whether renal vascular responses to other vasoactive agents (e.g. AngII) are similarly affected by the level of RAP remains to be determined.
Effect Of Amlodipine On Cardiopulmonary Performance In Volunteers
Authors: Lay L , Bjorksten Ar , Stainsby Gv , Blake Dw 
Published: March 2003

SUMMARY1. In order to exclude a significant effect of the calcium channel antagonist amlodipine on cardiopulmonary performance in normal subjects, we performed a double‐blind cross‐over study of amlodipine (10 mg daily for 2 weeks) on oxygen uptake and catecholamine responses during exercise in eight volunteers.2. Despite a therapeutic plasma concentration of amlodipine (22.8±9 ng/mL), there was no change in resting heart rate or blood pressure. Amlodipine did not cause significant change in oxygen uptake at the anaerobic threshold or at maximum exercise and there was also no change in heart rate or catecholamine responses.3. Although there was an awareness of peripheral vasodilation and reports of lethargy during the active treatment period, the volunteers had no objective evidence of a decrease in cardiopulmonary performance. We suggest that use of amlodipine as a vasodilator in the perioperative period would not add to the myocardial depressant effects of general anaesthesia in patients with normal cardiac function.
Proceedings of the Australian Physiological and Pharmacological Society Symposium: The Hypothalamus FETAL HYPOTHALAMUS–PITUITARY–ADRENAL AXIS ON THE ROAD TO PARTURITION
Authors: Schwartz Jeff , McMillen I Caroline 
Published: March 2003

SUMMARY1. Activity of the fetal hypothalamus–pituitary–adrenal (HPA) axis waxes and wanes as a function of gestational age.2. In a number of species, including sheep, at the end of gestation there is an increase in HPA activity, as characterized by an increase in fetal plasma glucocorticoids.3. To a certain degree, the hypothalamus, pituitary and adrenal all act autonomously and, therefore, may be thought of as contributing to the initiation of the signal that results in the increase in steroidogenesis before birth.4. Because it integrates sensory information from beyond as well as within the HPA axis and likely triggers developmental changes within the pituitary, the hypothalamus may be a ‘first among equals’ in being the ultimate source of triggering information for the HPA axis.
Type IV Phosphodiesterase Inhibitor Suppresses Insulin‐Dependent Myocardial Glucose Uptake
Authors: Imahashi Kenichi , Yoshioka Jun , Yamakita Tsuyoshi , Yamano Suzuyo , Kusuoka Hideo , Nishimura Tsunehiko 
Published: March 2003

SUMMARY1. Phosphodiesterase (PDE) IV has been localized at cardiomyocytes and the coronary vasculature and modulates cAMP, but the effect of PDE IV on myocardial glucose uptake has not been demonstrated.2. Glucose uptake in rat isolated hearts treated with the PDE IV inhibitor rolipram was measured by [31P] nuclear magnetic resonance spectroscopy.3. Under non‐stimulating conditions, glucose uptake was not significantly different between control and rolipram (1 μmol/L)‐treated rat hearts, whereas enhanced uptake in insulin‐stimulated conditions was significantly attenuated by rolipram.4. Phosphodiesterase IV inhibitor negatively affects insulin‐dependent myocardial glucose uptake.