bluuebunny/crossref_metadata_2025_split huggingface dataset:
MECHANISMS OF INSULIN RESISTANCE AND NEW PHARMACOLOGICAL APPROACHES TO METABOLISM AND DIABETIC COMPLICATIONS
Authors: Donnelly Richard , Qu Xianqin 
Published: June 2007

SUMMARY1. Resistance to insulin‐mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non‐insulin‐dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post‐receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of β3‐adrenoceptors (β3‐AR) in adipose tissue.2. Multiple lines of evidence suggest that isoform‐selective activation of PKC phosphorylates and down‐regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium‐independent isozymes (PKC‐ε and PKC‐θ) in the membrane fraction of skeletal muscle in fructose‐ and fat‐fed rat models of insulin resistance. In addition, there is separate evidence that glucose‐induced PKC activation plays an important role in the micro‐and macrovascular complications of diabetes.3. New pharmacological approaches to NIDDM and obesity have focused on insulin‐sensitizing agents (e.g. troglitazone), β3‐AR agonists, anti‐lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC‐β LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance.4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.
Experimental Biology 1997 Symposium on Neurobiology of Thennoregulation: Role of Stress: ETHANOL, BODY TEMPERATURE AND THERMOREGULATION
Authors: Crawshaw Larry I. , Wallace Helen , Crabbe John 
Published: June 2007

SUMMARY1. The effects of ethanol on body temperature (Tb) and on the regulator of Tb are reviewed.2. The first section considers how ethanol affects cellular function and how temperature modifies these effects.3. The next section reviews the effects of ethanol on Tb, covering both disruptive effects and effects on regulatory elements.4. The final section covers recent work that has made use of genetic techniques to elucidate specific aspects of how ethanol affects temperature regulation.
Experimental Biology 1997 Symposium on Neurobiology of Thermoregulation: Role of Stress: EFFECT OF GENDER ON THERMOREGULATION AND SURVIVAL OF HYPOXIC RATS
Authors: Wood Stephen C. , Stabenau Erich K. 
Published: June 2007

SUMMARY1. Hypothermia is a documented response to hypoxia but little is known about possible gender differences. Because female rats have a greater hypoxic ventilatory response than males, we hypothesized that females would be more tolerant of hypoxia. We studied 18 female and 18 male Long‐Evans rats.2. Radiotelemetry transmitters for body temperature (Tb) were implanted under general anaesthesia (90 mg/mL ketamine and 10 mg/mL xylazine; 0.1 mL/100 g body weight, i.p.).3. Rats were exposed to 21, 16, 12, 10, 8, 6, 4 and 2% O2 (balance N2) for 30 min each in chambers kept at either 31°C (clamped) or 20°C (hypothermic). Survival was defined as ataxic and unresponsive.4. Females were more hypoxia tolerant than males, often enduring 2% inspired O2 (13 km altitude).5. This was correlated with a lower Tb in the hypothermic group, but not in the clamped group.6. Hypothermia increased ‘survival’ of rats independent of gender.7. When Tb was clamped, female rats showed significantly greater survival than males.8. Thus, separate mechanisms (hypothermia or ventilation) may be acting to increase tolerance of clamped and hypothermic female rats to severe hypoxia.
Experimental Biology 1997 Symposium on Neurobiology of Thermoregulation: Role of Stress: HYPOTHERMIA AND PHYSIOLOGICAL CONTROL: THE RESPIRATORY SYSTEM
Authors: Frappell Peter 
Published: June 2007

SUMMARY1. Ventilation (V̇e) in unanaesthetized hypothermic animals remains tightly coupled to oxygen consumption (V̇o2) such that V̇e/V̇o2 remains constant despite changes in body temperature.2. Ventilatory responses to hypoxia would suggest that, relative to metabolic rate, the gain of the respiratory system is unaltered in hypothermic animals.3. Future studies should exercise care to ensure that the method applied in inducing hypothermia does not complicate ventilatory control and that the ability of the species to hibernate is taken into consideration.
INTRARENAL BLOOD FLOW: MICROVASCULAR ANATOMY AND THE REGULATION OF MEDULLARY PERFUSION
Authors: Pallone Thomas L. , Silldorff Erik P. , Turner Malcolm R. 
Published: June 2007

SUMMARY1. The microcirculation of the kidney is arranged in a manner that facilitates separation of blood flow to the cortex, outer medulla and inner medulla.2. Resistance vessels in the renal vascular circuit include arcuate and interlobular arteries, glomerular afferent and efferent arterioles and descending vasa recta.3. Vasoactive hormones that regulate smooth muscle cells of the renal circulation can originate outside the kidney (e.g. vasopressin), can be generated from nearby regions within the kidney (e.g. kinins, endothelins, adenosine) or they can be synthesized by adjacent endothelial cells (e.g. nitric oxide, prostacyclin, endothelins).4. Vasoactive hormones released into the renal inner medullary microcirculation may be trapped by countercurrent exchange to act upon descending vasa recta within outer medullary vascular bundles.5. Countercurrent blood flow within the renal medulla creates a hypoxic environment. Relative control of inner versus outer medullary blood flow may play a role to abrogate the hypoxia that arises from O2 consumption by the thick ascending limb of Henle.6. Cortical blood flow is autoregulated. In contrast, the extent of autoregulation of medullary blood flow appears to be influenced by the volume status of the animal. Lack of medullary autoregulation during volume expansion may be part of fundamental processes that regulate salt and water excretion.
MOLECULAR PHARMACOLOGY AND PHYSIOLOGY OF GLUTAMATE TRANSPORTERS IN THE CENTRAL NERVOUS SYSTEM
Authors: Vandenberg Robert J. 
Published: June 2007

SUMMARY1. Glutamate is the predominant excitatory neurotransmitter in the brain, but it is also a potent neurotoxin. Following release of glutamate from presynaptic vesicles into the synapse and activation of a variety of ionotropic and metabotropic glutamate receptors, glutamate is removed from the synapse. This is achieved through active uptake of glutamate by transporters located pre‐ and also post‐synaptically or, alternatively, glutamate can diffuse out of the synapse and be taken up by transporters located on the cell surface of glial cells.2. Complementary DNA encoding a number of glutamate transporters have recently been cloned and form a family of structurally related membrane proteins with a high degree of amino acid sequence conservation. Expression of the cloned glutamate transporters in various cell types has aided in the characterization of the functional properties of the different transporter subtypes.3. Glutamate transport is coupled to sodium, potassium and pH gradients across the cell membrane creating an electrogenic process. This allows transport to be measured using electrophysiological techniques, which has greatly aided in understanding some of the basic mechanisms of the transport process and has also allowed a detailed understanding of the molecular pharmacology of the different transporter subtypes.4. In the present review I shall discuss some of the recent advances in understanding the molecular basis for glutamate transporter function and then highlight some of the unanswered questions concerning the physiological roles of these proteins and suggest possible strategies for pharmacological manipulation of transporters for the treatment of neurological disorders.
AUTONOMIC NERVOUS SYSTEM AS A TARGET FOR CARDIOVASCULAR DRUGS
Authors: Bousquet P. , Monassier L. , Feldman J. 
Published: June 2007

1. Drugs acting within the autonomic nervous system (ANS) are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease (i.e. hyperkinetic borderline hypertension) a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate.2. Several classes of drugs acting within the central, as well as the peripheral ANS, are very efficient in treating hypertensive disease. One of these classes of drugs, the second generation of centrally acting drugs, has proved beneficial in this respect because, in addition to their therapeutic efficacy, these drugs are well tolerated.3. The central nervous system may also be the target for drugs with the potential to treat other cardiovascular diseases. Some recent experimental and clinical data supporting such new perspectives concerning idiopathic dysrhythmias, angina pectoris and congestive heart failure will be summarized.
CUTANEOUS VASOCONSTRICTION WITH ALERTING STIMULI IN RABBITS REFLECTS A PATTERNED REDISTRIBUTION OF CARDIAC OUTPUT
Authors: Blessing WW , Arnolda LF , Yu Y‐H 
Published: June 2007

SUMMARY1. In conscious rabbits, when alerting stimuli elicit vasoconstriction in the ear vascular bed, there is little or no associated change in cardiac output (CO), as measured by chronically implanted Doppler ultrasonic probes.2. Local anaesthetic injected around the base of the ear substantially diminished the degree of the vasoconstriction elicited during responses.3. Our results emphasize that selective cutaneous vasoconstriction, an integral part of the response to alerting stimuli in conscious animals, is part of a patterned redistribution of the CO, organized by the brain.
CONTROL OF SYMPATHETIC OUTFLOWS BY THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS
Authors: Coote JH , Yang Z. , Pyner S. , Deering J. 
Published: June 2007

SUMMARY1. The functional role of the paraventricular nucleus (PVN) has been examined by studying its connections with cardiovascular neurons in the medulla and spinal cord and its influence on activity in several sympathetic nerves.2. Chemical stimulation of neurons within the PVN can elicit pressor responses and can excite reticulo‐spinal vasomotor neurons in the rostral ventrolateral medulla (RVLM).3. The PVN‐RVLM excitation is blocked by kynurenic acid applied iontophoretically in the vicinity of RVLM‐spinal neurons, suggesting this is a glutamate‐dependent pathway.4. Electrical stimulation of PVN neurons evoked action potentials in RVLM neurons after 27 ms with a small variability.5. Anterograde and retrograde labelling of PVN and RVLM neurons revealed PVN terminals closely associated with RVLM‐spinal neurons and showed that the PVN is connected to the spinal cord via three pathways.6. Chemical activation of PVN neurons can produce a pattern of activation of cardiovascular neurons similar to that occurring in defence against plasma volume expansion.7. It is concluded that the PVN connections with the RVLM and spinal cord are important to a role in defending against life‐threatening disturbances.
EFFECTS OF LOCAL INHIBITION OF THE CARDIAC RENIN‐ANGIOTENSIN SYSTEM WITH CV‐11974 IN A CANINE ISCHAEMIA‐REPERFUSION MODEL
Authors: So Toshimitsu , Nakashima Yoshiyuki , Imamura Mitsuhide , Arakawa Kikuo 
Published: June 2007

SUMMARY1. To determine whether total interruption of the local cardiac renin‐angiotensin system by angiotensin II (AngII) receptor antagonist limits myocardial ischaemia, intracoronary (i.e.) or intravenous (i.v.) infusion of Angll receptor antagonists was compared in ischaemic dogs.2. Dogs subjected to 90min coronary artery occlusion and 270 min reperfusion assigned to saline (n= 10) or i.e. low dose (LD, n= 10), i.v. low dose (n= 10) or i.v. high dose (HD, n= 10) of AngII AT1‐receptor antagonist, CV‐11974. The CV‐11974 was infused from 15 min pre‐occlusion for 180 min. Cardiac and regional function, area at risk and infarct size were measured.3. Although i.e. CV‐11974 did not cause systemic haemodynamic changes, it abolished reduction in coronary blood flow induced by i.e. AngII injection. Elevation in LV end‐diastolic pressure during ischaemia was smaller in both i.e. and i.v.‐HD CV‐11974 dogs than in i.v.‐LD and control dogs. Regional wall thickening was not different among the four groups. With comparable area at risk, i.e. CV‐11974 reduced infarct size to the same extent as i.v.‐HD CV‐11974 (18 vs 21%), which was smaller than i.v.‐LD CV or the controls (38 and 42%).4. The results indicate that AngII receptor antagonist can reduce ischaemia‐reperfusion injury in experimental ischaemia. These cardioprotective effects might be mediated through direct inhibition of local angiotensin action in the heart. Local cardiac AngII formation may play a crucial role in cardiac injury during ischaemia and reperfusion.
EFFECT OF ANGIOTENSIN II RECEPTOR BLOCKADE ON THE INTERACTION BETWEEN ENALAPRILAT AND DOXAZOSIN IN RAT TAIL ARTERIES
Authors: Marwood John F. 
Published: June 2007

SUMMARY1. Previous work has shown that enalaprilat, an inhibitor of angiotensin‐converting enzyme (ACE), potentiated the actions of ai‐adrenoceptor antagonists; it was hypothesized that angiotensin II (Angll) modulated the activity of α1‐adrenoceptors. This hypothesis was tested in Sprague‐Dawley rat isolated perfused tail arteries using the AT1receptor antagonist losartan and the AT2receptor antagonist PD123319.2. Losartan had no oti‐adrenoceptor antagonist effects at concentrations below 1 μmol/L. Similarly, losartan (0.1 μmol/L) had no effect on the α1‐adrenoceptor antagonist action of doxazosin (1,10 nmol/L) nor on the potentiation of doxazosin by enalaprilat (1μmol/L).3. PD123319 (0.1 μmol/L) had no α1‐adrenoceptor antagonist effect but altered the mode of action of the α1‐adrenoceptor antagonist doxazosin: PD123319 changed doxazosin from a competitive to a non‐competitive antagonist, as evidenced by the reduced slope of the dose‐response curve for the α1‐adrenoceptor agonist phenylephrine.4. These results suggest that Angll can modulate α1‐adrenoceptor function in rat tail arteries via an indirect action at AT2receptors. However, the present results do not rule out the involvement of bradykinin, endothelin or prostaglandin in the modulation of α1‐adrenoceptor function by angiotensin II.
PHARMACOLOGICAL STIMULATION OF ARTERIAL CHEMORECEPTORS IN CONSCIOUS RATS PRODUCES DIFFERENTIAL RESPONSES IN RENAL CORTICAL AND MEDULLARY BLOOD FLOW
Authors: Ledderhos Carla , Gross Volkmar , Jr Allen W Cowley 
Published: June 2007

SUMMARY1. There have been no previously published data regarding intrarenal blood flow distribution in acute whole‐body hypoxic hypoxia and/or arterial chemoreceptor stimulation in normoxic mammals.2. Cortical and medullary blood flows were measured simultaneously before and in response to pharmacological stimulation of peripheral arterial chemoreceptors by i.v. injection of almitrine bismesylate (0.25 mg/kg).3. Arterial chemoreceptor excitation reduced cortical blood flow but only in innervated kidneys. An effect on medullary blood flow was observed in neither innervated nor denervated kidneys.4. These data indicate that renal cortical and medullary blood flows react differently to arterial chemoreceptor stimulation.
COMPARISON OF HAEMODYNAMIC RESPONSES TO CILNIDIPINE AND NICARDIPINE IN AN EXPERIMENTAL MODEL OF ACUTE CONGESTIVE HEART FAILURE
Authors: Noguchi Katsuhiko , Matsuzaki Toshihiro , Koyama Tomoyuki , Itomine Tatsushi , Sakanashi Matao 
Published: June 2007

SUMMARY1. The haemodynamic effects of cilnidipine, a new calcium channel blocker, were examined in a canine model of acute congestive heart failure and were compared with those of nicardipine at equihypotensive doses.2. The model was prepared by injections of saponin into coronary arteries of anaesthetized open‐chest dogs followed by volume loading and continuous i.v. infusion of methoxamine. After the treatment, aortic blood flow (AoF) and left ventricular dP/dt markedly decreased, while left ventricular end‐diastolic pressure (LVEDP), right atrial pressure and systemic vascular resistance (SVR) increased. Cilnidipine (0.3,1.0 and 3.0 μ/kg per min), nicardipine (0.3, 1.0 and 3.0 (μ/kg per min) or the respective vehicle was given i.v. after accomplishment of heart failure.3. These drugs both produced a comparable reduction in aortic pressure and an increase in AoF associated with profound decreases in LVEDP, SVR and coronary vascular resistance. In contrast, administration of nicardipine was associated with significant increases in heart rate and cardiac contractility but that of cilnidipine was not.4. These results indicate that cilnidipine as well as nicardipine can exert beneficial haemodynamic effects in a model of acute heart failure probably through lessening afterload and cilnidipine may moderate reflex‐induced sympathetic stimulation.
ELIMINATION, BUT NOT ACCUMULATION, OF METOPROLOL BY RAT ISOLATED PERFUSED HEART IS SELECTIVELY IMPAIRED BY HYPOXIA
Authors: Horowitz Rebecca H Ritchie and John D. 
Published: June 2007

SUMMARY1. The influence of hypoxia on the time course of regional myocardial accumulation and elimination of the β1‐adrenoceptor antagonist metoprolol was investigated by a spontaneously beating rat isolated perfused heart preparation.2. Myocardial metoprolol content was maximal at 2 min in the left and right ventricles and atria. Neither the extent nor the time of maximal myocardial metoprolol content was significantly influenced by the induction of hypoxia. However, maximal myocardial metoprolol content in both atria and right ventricles was significantly higher than that in the left ventricular samples (P<0.02; one‐factor analysis of variance, 17 d.f.).3. Elimination of metoprolol (as indicated from residual myocardial metoprolol content at 10 min) was impaired in hypoxic left ventricles (P<0.01 vs normoxia; unpaired t‐test, 10 d.f.) but not in right ventricles or atria. This variation in myocardial metoprolol disposition was not apparent from examination of serial metoprolol concentrations in coronary perfusate.4. Hypoxia selectively impaired the elimination of metoprolol from the left ventricle, but not the process of drug accumulation, by any region of myocardium. It remains to be determined whether this reflects regional variation in the extent of micro‐circulatory impairment associated with hypoxia.
EVIDENCE FOR THE PRESENCE OF BOTH P1 AND P2 PURINOCEPTORS IN THE RAT MYOMETRIUM
Authors: Gillman Tracey A. , Pennefather Jocelyn N. 
Published: June 2007

SUMMARY1. Adenosine, adenosine triphosphate (ATP) and some stable analogues of adenosine inhibited field stimulation‐induced contractions of the uterus from rats treated with oestradiol cypionate (20 μg/kg, s.c.) 1 day previously. Adenosine was twice as potent as ATP; both were potentiated by dipyridamole (10 μmol/L).2. The order of agonist potency of adenosine and its analogues was: 5′‐N‐ethyIcarboxamidoadenosine (NECA) >N6‐cyclohexyl‐adenosine ≥ R‐phenylisopropyladenosine = s‐phenylisopropyl‐adenosine = 2‐chIoroadenosine ≥ adenosine ≥ ATP ≫ 2‐p‐(2‐carboxyethyl) phenethylarnino‐5′‐N‐ethylcarboxamido‐adenosine. This order suggests the presence of P1 purinoceptors of the A2B subtype.3. Responses to agonists were antagonized to differing extents by the P1 purinoceptor antagonist 8‐phenyltheophylline (10μ‐mol/L).4. In uterine preparations from rats pretreated for 2 days with oestrogen (20 μg/kg, s.c.) and for 1 day with progesterone (3 mg/animal, s.c), the inhibitory potencies of adenosine and NECA were reduced, indicating hormonal regulation of uterine responsiveness to P1 purinoceptor agonists.5. Stable analogues of ATP caused contractions of unstimulated myometrial preparations from oestrogen‐treated animals, indicating activation of a P2 purinoceptor, possibly of the P2x subtype, because the relative order of potency was α,β‐methylene ATP> β, γ‐methylene ATP = ATP = 2‐methylthioATP.
NEUROPEPTIDE Y AND MESENTERIC SYMPATHETIC VASOCONSTRICTION IN PREGNANT AND NON‐PREGNANT WISTAR‐KYOTO RATS
Authors: Chu ZM , Beilin LJ 
Published: June 2007

SUMMARY1. We have investigated the role of neuropeptide Y (NPY) in sympathetic vasoconstriction and its possible contribution to decreased mesenteric vasoconstrictor responses to electrical field stimulation (EFS) in pregnancy in vivo using an in situ blood‐perfused mesenteric preparation in 18‐20 day pregnant and age‐matched non‐pregnant Wistar‐Kyoto (WKY) rats.2. Mean blood pressure (BP) was decreased in pregnant compared with non‐pregnant rats. Mesenteric basal perfusion pressure (PP) was not significantly reduced in pregnancy. BIBP 3226, a specific NPY Yi receptor antagonist, did not affect mean BP or mesenteric basal PP in pregnant or non‐pregnant animals.3. Mesenteric vasoconstrictor responses to EFS were blunted in pregnant compared with non‐pregnant controls. BIBP 3226 significantly suppressed mesenteric vasoconstrictor responses to EFS in both pregnant and non‐pregnant animals. Decreased mesenteric responses to EFS in pregnancy were still evident following NPY Yi receptor blockade.4. These results suggest that endogenous NPY plays a role in rat mesenteric sympathetic vasoconstriction in vivo. However, NPY is unlikely to be responsible for the impairment of EFS‐induced mesenteric vasoconstriction in pregnant WKY rats.
DEVELOPMENT OF A NEW ASSAY FOR MEASUREMENT OF TOTAL ANGIOTENSIN‐CONVERTING ENZYME AFTER INHIBITION
Authors: Yang Y. , Macdonald GJ 
Published: June 2007

SUMMARY1. We set out to develop a simple, rapid, highly sensitive and reproducible assay to quantify total angiotensin‐converting enzyme (ACE) in serum and tissues after ACE inhibition.2. Total ACE was measured by dissociating ACE inhibitor from the enzyme using zinc chelation (EDTA). The enzyme reconstituted with zinc ion (ZnSO4) was then measured by enzymatic fluorimetric assay. Angiotensin‐converting enzyme inhibition was produced in vitro by incubation of enalaprilat or perindoprilat with human serum or cell membranes from rat heart. To achieve the highest recovery rate, we studied concentrations of EDTA from 1 to 300 mmol/L with a pH range from 4 to 13, where the incubation times of EDTA were between 1 and 12 h. After washing off ACE inhibitor and excess EDTA, the resulting concentrates and pellets were then resuspended with Tris buffer containing ZnSO4 to restore ACE activity.3. The optimal assay conditions to dissociate the drug from the enzyme were 300 mmol/L EDTA in Tris buffer at pH 11 for 12 h with cell membranes and 23 mmol/L EDTA at the same pH incubated for 4 h with serum. The recovery of ACE activity was 81.7±15.8 and 97.3±2.9% in tissues and serum, respectively. Intra‐ and interassay variability coefficients were 5.6 and 12.8% in tissue, respectively, 3.2 and 13.0% in serum, respectively. The method allows quantification of ACE in 100 μ.L or less serum and 20 mg or less tissue.4. The total ACE concentration after ACE inhibition can be determined by this assay, which is suitable for micro‐sampling studies of both tissue and serum ACE levels.