bluuebunny/crossref_metadata_2025_split huggingface dataset:
USE OF MURINE MUTANTS TO STUDY GLYCINE RECEPTOR FUNCTION
Authors: Callister Rj , Schofield Pr , Sah P 
Published: March 2003

SUMMARY1. The accompanying articles in this symposium describe several different approaches used to examine the function of glycine and GABA receptors, including pharmacology and neurochemistry, permeability and agonist‐binding approaches, the use of mutated recombinant receptors and monoclonal antibody staining to examine receptor distribution on neurons.2. The present review focuses on the use of another, quite different, approach: the use of murine mutants, spasmodic and spastic, to study the function of native glycine receptors at synaptic connections within the central nervous system.
BUILDING NEW FUNCTION INTO GLYCINE RECEPTORS: A STRUCTURAL MODEL FOR THE ACTIVATION OF THE GLYCINE‐GATED CHLORIDE CHANNEL
Authors: Lynch Joseph W , Han Nian‐lin R , Schofield Peter R 
Published: March 2003

SUMMARY1. The glycine receptor chloride channel mediates inhibitory neurotransmission and is a member of the ligand‐gated ion channel superfamily, which includes the nicotinic acetylcholine receptor channel.2. Activation of these channels involves a movement of the pore‐lining second membrane‐spanning domain with respect to the remainder of the protein.3. The present review considers the evidence that the loops that connect this domain with the rest of the protein act as crucial components of the channel activation mechanism.
PROLONGED HYPOXIC STRESS INCREASES ADRENAL CHOLESTEROL RESERVE IN RATS WITHOUT CAUSING ADRENAL HYPERTROPHY
Authors: Cheng Behling , Abraham Susamma , Thakkar Jitendra , Kowal Jerome 
Published: March 2003

SUMMARY1. It is known that, in rats, hypoxia stimulates adrenal steroidogenesis, but our understanding of the hypoxic effect on the glandular parameters remains incomplete.2. Adrenals were collected and analysed from rats that had been exposed to hypoxic conditions for 3 weeks.3. The results reveal increased adrenal concentrations of corticosterone, free cholesterol and total cholesterol without a change in glandular weight and protein concentration. The increased total cholesterol is primarily associated with enriched cholesteryl adrenate (CE22 : 4), cholesteryl arachidonate (CE20 : 4) and cholesteryl oleate (CE18 : 1).
RENAL ARTERIOLAR CONTRACTILE RESPONSES TO ANGIOTENSIN II IN RATS WITH POORLY CONTROLLED DIABETES MELLITUS
Authors: Carmines Pamela K , Ohishi Kazuhisa 
Published: March 2003

SUMMARY1. Experiments were performed to test the hypothesis that renal arteriolar responses to angiotensin (Ang)II are altered in insulin‐dependent diabetes mellitus.2. Male Sprague‐Dawley rats were treated with streptozotocin (STZ; 65 mg/kg, i.v) or 0.9% NaCl vehicle (Sham). Partial insulin replacement maintained blood glucose levels at 422±6 mg/dL (STZ rats) for the ensuing 2 week period (86±4 mg/dL in Sham rats). The in vitro blood‐perfused juxtamedullary nephron technique was used to study renal arteriolar diameter responses to exogenous AngII or K+‐induced membrane depolarization.3. Baseline afferent arteriolar diameter did not differ between kidneys harvested from Sham and STZ rats; however, constrictor responses to AngII were accentuated in kidneys from diabetic rats. During exposure to 10 nmol/L AngII, afferent diameter decreased by 37±5 and 18±4% in STZ and Sham kidneys, respectively. Efferent arterioles from Sham and STZ rats did not differ with regard to either baseline diameter or AngII responsiveness.4. In experiments assessing afferent arteriolar responsiveness to membrane depolarization, 40 mmol/L K+ decreased lumen diameter by 73±11% in kidneys from Sham rats; however, the same depolarizing stimulus only reduced afferent diameter by 28±7% in STZ kidneys.5. We conclude that afferent (but not efferent) arteriolar AngII responsiveness is increased during the early stages of poorly controlled diabetes mellitus in the rat. The exaggerated afferent arteriolar responsiveness to AngII occurs despite reduced sensitivity to membrane depolarization, suggesting that the emergence of alternative signalling processes or alterations in vasoactive modulator influences may underlie this phenomenon.
SIMVASTATIN INHIBITS CARDIAC HYPERTROPHY AND ANGIOTENSIN‐CONVERTING ENZYME ACTIVITY IN RATS WITH AORTIC STENOSIS
Authors: Luo Jian‐Dong , Zhang Wei‐Wen , Zhang Gui‐Ping , Guan Jin‐Xia , Chen Xiu 
Published: March 2003

1. In the present study, we tested the hypothesis that long‐term administration of the hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor simvastatin may regress hypertrophy and the possible effect of simvastatin on angiotensin‐converting enzyme (ACE) activity in rats with pressure‐overload cardiac hypertrophy.2. Pressure‐overload left ventricular hypertrophy (LVH) of rats was induced by part coarctation of the abdominal aorta; a sham‐operated group served as the control. Six weeks after operation, animals were divided into three groups and an 8 week treatment period was insitgated as follows: (i) the simvastatin treatment group received simvastatin at 3.6 mg/kg per day, p.o.; (ii) the ACE inhibitor group received captopril at 50 mg/kg per day, p.o.; and (iii) the LVH control group received no drug treatment.3. At the end of the treatment period, left ventricular systolic pressure (LVSP) and left ventricular end‐diastolic pressure (LVEDP) were monitored in vivo. Diastolic pressure–volume relationships were evaluated in a Langendorff preparation with a balloon‐in‐left ventricle (LV) heart. Myocyte cell width was measured. Angiotensin‐converting enzyme activity and angiotensin (Ang)II and hydroxyproline contents of the LV were determined.4. At the end of the experiments, LVH was established in the LVH control group by increases in LV weight, LV weight/bodyweight ratio, LV weight/right ventricle weight ratio, LV myocyte cell width, LVSP and LVEDP by 40, 26, 19, 61, 56 and 59%, respectively (all P < 0.01), compared with the sham‐operated group. In the simvastatin‐treated and ACE inhibitor groups all these parameters were significantly reduced compared with sham‐operated controls. In the LVH control group, ACE activity and AngII and hydroxyproline contents of LV tissue increased by 180, 123 and 70, respectively (all P < 0.01), compared with the sham‐operated group. Compared with the LVH group, in the simvastatin‐treated and ACE inhibitor groups ACE activity was reduced by 36 (P < 0.05) and 48% (P < 0.01), respectively, AngII content was reduced by 11 (P < 0.05) and 43% (P < 0.01), respectively, and hydroxyproline content was reduced by 23 (P < 0.01) and 10% (P < 0.05), respectively.5. For the first time, the results of the present study demonstrate that simvastatin significantly reduces LVH, cardiac tissue ACE activity and improves LV performance in pressure‐ overloaded rats. Because, compared with captopril, simvastatin is more potent in its reduction of LVH and less potent in its inhibition of ACE activity, the mechanism of its antihypertrophic action, in addition to ACE inhibition, may involve inhibition of the mevalonic acid pathway, the main target of action of statins. Thus, HMG‐CoA reductase inhibitors may be beneficial for the clinical treatment of cardiac hypertrophy.
SUPRANORMAL NATRIURETIC RESPONSE TO VOLUME EXPANSION IN VAGOTOMIZED AND RENAL‐DENERVATED RATS
Authors: Rodríguez‐Martínez Manuel , Brito‐Orta Dolores 
Published: March 2003

SUMMARY1. To investigate the participation of both vagal cardiopulmonary baroreceptor activity and efferent renal sympathetic nerve activity (ERSNA) in the natriuretic response to saline volume expansion (SVE), three series of experiments were undertaken in anaesthetized rats.2. In the first two series of experiments, the natriuretic (series A) and ERSNA (series B) responses to SVE were evaluated in both sham operated and cervical bilateral vagotomized rats. The acute experiment consisted of two baseline (BL) periods, treatment (sham control (CTR) or real cervical bilateral vagotomy), a volume expansion phase (Ringer’s solution, 10% bodyweight) and a postexpansion phase. The results of these two series indicate that vagotomy significantly enhances basal ERSNA (37±8%; P < 0.05 vs BL) and significantly attenuates the renal sympathoinhibitory response (by approximately 50%; P < 0.05 vs CTR) but not the natriuretic response to SVE, suggesting the potential expression of a vagotomy induced compensatory natriuretic mechanism.3. To assess this, the natriuretic response to SVE was evaluated in chronic sham operated or renal denervated groups of rats in which vagotomy was or was not performed (series C). There were no differences among groups in either systemic haemodynamics or plasma protein concentration. Vagotomy plus chronic renal denervation induced a supranormal natriuretic and diuretic response (approximately 30%; P < 0.01) to SVE when compared with similar natriuretic and diuretic responses of the remaining groups.4. These data support the idea that, in intact rats on a normal sodium diet, neither cardiopulmonary baroreceptors nor renal nerves are necessary for the elimination of an acute intravenous isotonic sodium load and indicate that during SVE the activation of vagal cardiopulmonary baroreceptors exerts an inhibitory effect on both ERSNA and the expression of a natriuretic mechanism. Such a natriuretic mechanism is expressed only when SVE is induced in vagotomized rats (compensating for the vagotomy mediated antinatriuretic effects of an enhanced ERSNA), but is unmasked only when, in addition, renal nerves are chronically transected. All of this offers an efficient element of safety in eliminating an acute isotonic sodium load when cardiopulmonary baroreceptors are severed.
Viral‐Mediated Gene Delivery Of Constitutively Activated GΑS Alters Vasoreactivity
Authors: Schutzer William E , Watts Val J , Chapman Justin , Cumbay Medhane G , Neve Kim A , Neve Rachael L , Mader Scott L 
Published: March 2003

SUMMARY1. Decline in β‐adrenoceptor (β‐AR)‐mediated function occurs with increasing age, as well as in multiple disease conditions. The mechanisms responsible for this decline include alterations in β‐AR itself, β‐AR coupling proteins, such as G‐proteins, or other β‐AR‐linked proteins, such as G‐protein receptor kinases and/or phosphatases.2. The present study examines the physiological effects of in vitro transfer of constitutively activated Gαs (Gαs‐Q227L) to both cultured vascular smooth muscle cells (VSMC) and whole aortic tissue of 6‐month‐old (adult) animals via a replication‐deficient Herpes simplex virus (HSV) vector. These studies were conducted to provide a model for future examination of the role of Gαs in the age‐related decline in β‐AR‐mediated vasorelaxation.3. Gene transfer was confirmed by western blotting for specific proteins. Aortic tissue infected with HSV–Gαs‐Q227L had reduced phenylephrine‐induced contraction and enhanced isoproterenol‐stimulated vasorelaxation. Infection of cultured VSMC with HSV–Gαs‐Q227L increased both basal‐ and isoproterenol‐stimulated cAMP accumulation, whereas forskolin‐stimulated cAMP production was unchanged.4. These results implicate Gαs as a target for further investigation in age‐related changes in vascular reactivity and support the use of viral‐mediated gene transfer as an effective tool to study adrenergic signal transduction and physiology in vascular tissue.
Imaging And Nano‐Manipulation Of Single Actomyosin Motors At Work
Authors: Ishii Yoshiharu , Kimura Yuji , Kitamura Kazuo , Tanaka Hiroto , Wazawa Tetsuichi , Yanagida Toshio 
Published: March 2003

SUMMARY1. Muscle contraction is achieved by the sliding movement of myosin and actin using the energy of ATPase.2. Our research has focused on the question of how chemical energy is used to perform mechanical work. Recent developments of single molecule imaging and manipulation techniques have allowed us to study the chemical and mechanical events at a molecular level.3. There are many lines of evidence that show that the energy liberated from ATPase is stored in the actomyosin molecules for later use.4. The displacement produced by a single ATP molecule is made up of several steps, each of 5.3 nm. Sometimes the mechanical event is delayed after the ADP is released from myosin.5. This storage of energy may be explained by a slow conformational transition between the metastable states of the proteins. This suggestion has been supported by results obtained using single‐molecule fluorescence spectroscopy.
Effects Of β‐Adrenoceptor Stimulation On Pacing‐Induced Failure Of Dog Hypertrophic Hearts
Authors: Huang Mark W , Leone Richard J Leone , Weiss Harvey R , Tse James , Scholz Peter M 
Published: March 2003

SUMMARY1. We tested the hypothesis that the transition to pacing‐induced failure in hypertrophic hearts would result in reduced functional and metabolic responses to β‐adrenoceptor stimulation.2. Isoproterenol (ISO; 0.1 μg/kg per min) was infused into a coronary artery in five anaesthetized open‐chest control, five aortic stenosis‐induced left ventricular hypertrophy (LVH) and five LVH pacing‐induced failure dogs.3. In both control and LVH dogs, but not in failure dogs, ISO significantly increased local regional work (1923±665 vs 2656±715, 1185±286 vs 1906±562 and 835±106 vs 849± 216 g.mm/min, respectively), force (11.1±1.4 vs 16.9±2.6, 8.6±1.5 vs 13.7±2.3 and 12.2±1.1 vs 11.0±1.8 g, respectively) and myocardial O2 consumption (7.3±2.0 vs 10.0±1.5, 8.2±1.6 vs 11.6±2.6 and 4.4±1.5 vs 5.5±1.8 mL O2/min per 100 g, respectively).4. Isoproterenol also significantly increased cAMP in control and LVH dogs (474±67 vs 600±91 and 473±34 vs 619± 53 pmol/g, respectively). In heart failure, cAMP was significantly lower and there was no significant increase in cAMP in response to ISO (245±43 vs 314±40 pmol/g, respectively).5. We conclude that there were no significant myocardial functional, O2 consumption or cAMP responses to ISO after the transition from hypertrophy to cardiac failure.
Pretreatment With Ramiprilat Induces Cardioprotection Against Free Radical Injury In Guinea‐Pig Isolated Heart: Involvement Of Bradykinin, Protein Kinase C And Prostaglandins
Authors: Jin Zhu‐Qiu , Chen Xiu 
Published: March 2003

SUMMARY1. Pretreatment with ramiprilat, an angiotensin‐converting enzyme (ACE) inhibitor, induced cardioprotection and its possible mechanism of action was investigated in guinea‐pig Langendorff perfused heart.2. Superoxide anion (•O2–), produced by hypoxanthine and xanthine oxidase, and the 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) free radical were used for triggering free radical injury in cardiac tissue.3. 1,1‐Diphenyl‐2‐picryl‐hydrazyl and •O2– significantly reduced left ventricular developed pressure (LVDP), ±dP/dtmax, heart rate and coronary flow. Left ventricular end‐diastolic pressure (LVEDP) was elevated and lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid‐reactive substances (TBARS) formation were significantly increased.4. Pretreatment with ramiprilat induced cardioprotection against DPPH and •O2– free radical injury. Cardiac functions (LVDP, LVEDP and ±dP/dtmax) were significantly improved. Both LDH and TBARS were reduced.5. HOE 140 (a selective bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC) inhibitor) and indomethacin (a cyclo‐oxygenase inhibitor) all abolished the cardiac protective effect of ramiprilat. However, NG‐nitro‐
L‐arginine methyl ester, a nitric oxide synthase inhibitor, had no effect.6. In conclusion, ramiprilat pretreatment induces cardioprotection against either DPPH or •O2– free radical injury. The protective effect depends on activation of B2 receptors and PKC. Prostaglandin synthesis is also involved.
Tissue Distribution Of α‐Tocopherol In Nephrotic Rats
Authors: Medina‐Campos On , Mancera J , Pedraza‐Chaverrí J 
Published: March 2003

SUMMARY1. Reactive oxygen species are involved in the pathogen‐ esis of puromycin aminonucleoside (PAN) nephrosis and α‐tocopherol is one of the major anti‐oxidants in the body.2. In the present study, we measured the levels of α‐tocopherol by high‐performance liquid chromatography in the plasma and in nine tissues of control and nephrotic rats obtained 10 days after either 0.9% saline solution or PAN injection, respectively.3. In nephrotic rats, α‐tocopherol levels increased four‐ fold in plasma; however, the molar ratio of α‐tocopherol/ cholesterol remained unchanged, suggesting that the increase in α‐tocopherol content was attributable to an increase in plasma lipid concentration.4. In nephrotic rats, the α‐tocopherol/cholesterol ratio increased 1.33‐fold in adrenal glands and 1.34‐fold in the testis, but remained unchanged in heart, spleen, liver, kidney lung, brain and muscle.5. These data suggest that, in PAN nephrotic rats, there are alterations in the distribution of α‐tocopherol and there is no deficiency of α‐tocopherol in plasma or tissues.
Presynaptic Inhibitory Actions Of Lignocaine In Canine Isolated, Blood‐Perfused Atrial Preparations
Authors: Tsuboi Masato , Chiba Shigetoshi 
Published: March 2003

SUMMARY1. Cardiac effects of lignocaine on sinoatrial nodal pacemaker activity and atrial contractility were investigated in five canine isolated, blood‐perfused right atria that were perfused with heparinized blood from support dogs. The effects of lignocaine on responses to intracardiac nerve stimulation and administered acetylcholine and noradrenaline were also examined.2. Lignocaine was injected into the support dog intravenously or administered selectively to the sinus node artery of the isolated atrium. At doses that did not produce significant depressor action (0.3, 1.0 and 3.0 mg/kg), lignocaine produced no significant changes in heart rate. A large dose of 10 mg/kg lignocaine caused significant depressor effects and slight bradycardia. Direct administration of lignocaine (0.3, 1.0, 3.0, 10.0 and 30.0 μmol) into the sinus node artery of the isolated atrium consistently caused slight negative chronotropic and rather marked negative inotropic effects.3. After treatment with a relatively large dose of lignocaine, electrical stimulation‐induced negative chronotropic and inotropic responses were significantly inhibited in a dose‐related manner, but positive chronotropic and inotropic responses were slightly depressed only at an extremely high dose of lignocaine (10.0 μmol).4. Noradrenaline‐induced positive chronotropic and inotropic effects were not modified by any doses of lignocaine used (0.3, 1.0, 3.0 and 10.0 μmol). Acetylcholine‐induced negative chronotropic and inotropic effects were slightly, but significantly, depressed by 10 μmol lignocaine.5. These results suggest that a relatively large dose of lignocaine has a dominant presynaptic inhibitory action, particularly on the parasympathetic component.
Differential Secretion Of Adrenaline And Noradrenaline In Response To Various Secretagogues From Bovine Chromaffin Cells
Authors: Kuwashima Haruhiro , Matsumura Chiaki , Kimura Tomohiko 
Published: March 2003

SUMMARY1. Differential secretion of adrenaline (Adr) and noradrenaline (NA) in response to various secretagogues was studied in bovine adrenal chromaffin cells.2. Acetylcholine (ACh; 3–300 μmol/L), 1,1‐dimethyl‐ 4‐phenyl‐piperazinum (DMPP; 1–100 μmol/L), high K+ (20–60 mmol/L), calcimycin (1–100 μmol/L), histamine (0.3–30 μmol/L) and angiotensin (Ang)II (0.3–30 μmol/L) induced the secretion of a 1.3–2‐fold greater percentage of NA stores than Adr stores in intact cells.3. In β‐escin‐permeabilized cells, Ca2+ (0.1–30 μmol/L) induced a greater secretion of Adr and NA in the presence of MgATP (2 mmol/L) than in the absence of MgATP. The percentage of NA secreted was 1.4‐ and 1.5‐fold greater than that of Adr in the presence and absence of MgATP, respectively.4. The ATP‐independent phase of the Ca2+‐dependent exocytosis is thought to be associated with the final step that ultimately leads to fusion, while the ATP‐dependent phase is thought to be associated with the vesicle priming reaction. Therefore, the preferential secretion of NA in response to ACh, DMPP, high K+, calcimycin, histamine and AngII may be due, at least in part, to the greater effectiveness of Ca2+ in producing exocytosis in NA‐containing cells.
Quality Use Of Medicines: Where Does Pharmacology‘End’? Invited Ascept Lecture
Authors: Smith Aj 
Published: March 2003

SUMMARY1. Pharmacology can be defined very narrowly (e.g. as solely a laboratory based specialty) or more broadly to include issues surrounding rational drug use in the community.2. While the hypothetio–deductive approach is more clearly in evidence in laboratory and clinical pharmacological experimentation, it is no less important in the comparatively less‐well charted area of drug use in the community.3. Just as laboratory pharmacology has built new partnerships with molecular biology and genetics, the exploration of community drug use brings pharmacologists into partnership with other disciplines (epidemiology, economics, behavioural science) and other sectors (consumers, government, health professionals and industry).4. Implementing Australia’s Quality Use of Medicines Policy (1992) has led to vigorous exploration of issues and problems in medicinal drug use in the community and much scientific study of causes and potential interventions to improve the situation.5. The Australian National Prescribing Service (1998) is attempting to bring an evidence‐based approach to the many facets of prescribing and drug use, by prescribers and consumers alike.6. Innovation commonly occurs at the interface between the boundaries of traditional disciplines.
Tris Lipidation: A Chemically Flexible Technology For Modifying The Delivery Of Drugs and Genes
Authors: Lockett T , Reilly W , Manthey M , Wells X , Cameron F , Moghaddam M , Johnston J , Smith K , Francis C , Yang Q , Whittaker R 
Published: March 2003

SUMMARY1. One of the major challenges in the development of pharmaceuticals is their formulation with other materials to give them the desired bioavailability profile when administered into the body.2. We have developed a flexible platform technology (Tris lipidation) to simply and effectively alter the lipophilicity of drugs. As implied by the name, the technology uses the common buffer Tris as a linker between the drugs of interest and a domain of variable hydrophobicity.3. We demonstrate, using a mouse melanoma model, that Tris‐lipidated conjugates of the widely used cytotoxic and anti‐inflammatory drug methotrexate (MTX) display enhanced potency in the local treatment of tumours and reduced systemic toxicity when compared with the unconjugated drug.4. With genes now being predicted to be the pharmaceuticals of the future, we show that Tris‐lipidated cationic peptides can efficiently deliver DNA into (transfect) cells in culture. Furthermore, by comparing the abilities of variants of these Tris‐based cationic lipids to transfect cultured cells, we demonstrate that modifications made to variable regions of Tris‐lipidated compounds can dramatically alter their delivery profiles.
Modelling The Neural Control Of Intrarenal Blood Flow
Authors: Navakatikyan Michael A , Leonard Bridget L , Evans Roger G , Malpas Simon C 
Published: March 2003

SUMMARY1. The aim of the present study was to produce a mathematical model that describes the way dynamic changes in renal sympathetic nerve activity affect renal, cortical and medullary blood flow.2. Cortical blood flow (CBF) and medullary blood flow (MBF) were measured using laser‐Doppler flowmetry and (total) renal blood flow (RBF) was measured by transit‐time flowmetry in six pentobarbitone‐anaesthetized rabbits. The renal nerves were stimulated with rectangular pulses of 2 msec width and constant voltage at frequencies of 0.5, 1, 1.5, 2 and 3 Hz.3. An exponential function with two parameters was applied; steady state gain and a dynamic constant for the blood flow reduction with stimulation. The steady state gain coefficients were similar for RBF and CBF, but significantly less for MBF. The time taken to reach minimum flow was less for MBF than for RBF and CBF.4. The model parameters indicate that there is differential neural control of CBF and MBF.