bluuebunny/crossref_metadata_2025 huggingface dataset:
TARGETED DRUG DELIVERY TO THE SKIN AND DEEPER TISSUES: ROLE OF PHYSIOLOGY, SOLUTE STRUCTURE AND DISEASE
Authors: Roberts MS
Published: June 2007

1. Drug delivery through the skin has been used to target the epidermis, dermis and deeper tissues and for systemic delivery. The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region. The polarity of the intercellular region appears to be similar to butanol, with the diffusion of solutes being hindered by saturable hydrogen bonding to the polar head groups of the ceramides, fatty acids and other intercellular lipids. Accordingly, the permeability of the more lipophilic solutes is greatest from aqueous solutions, whereas polar solute permeability is favoured by hydrocarbon‐based vehicles.

2. The skin is capable of metabolizing many substances and, through its microvasculature, limits the transport of most substances into regions below th. dermis.

3. Although the flux of solutes through the skin should be identical for different vehicles when the solute exists as a saturated solution, the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It is therefore desirable that the regulatory standards required for the bio‐equivalence of topical products include skin studies.

4. Deep tissue penetration can be related to solute protein binding, solute molecular size and dermal bloo. flow.

5. Iontophoresis is a promising area of skin drug delivery, especially for ionized solutes and when a rapid effect i. required.

6. In general, psoriasis and other skin diseases facilitate drug delivery through th. skin.

7. It is concluded that the variability in skin permeability remains an obstacle in optimizing drug delivery by thi. route.
EVIDENCE FOR DIRECT INTERACTION OF KETAMINE WITH α‐ AND β2‐ADRENOCEPTORS
Authors: Bevan RK , Rose MA , Duggan KA
Published: June 2007

1. Ketamine has a number of effects that suggest that it may interact with α‐ and β‐adrenoceptors. To date, the experimental evidence for this has been indirect and has been based on physiological studies using competitive blocking agents. In the present study we sought to determine from receptor binding studies whether ketamine binds directly to α‐ and β‐adrenoceptors.

2. Membrane preparations o. α1‐ and β2‐adrenergic binding sites were obtained from urinary bladder and urethrae of sheep. These binding sites were characterized by saturation analyses using [3H]‐prazosin for α1‐adrenoceptor binding sites and [125I]‐cyanopindolol (CYP) for the β2‐adrenoceptor binding sites. The receptors were further characterized by displacement studies using selective and non‐selective antagonists.

3. Studies in which ketamine was used to displac. [3H]‐prazosin revealed a Kd of 3.40±1.23× 10−3 mol/L for ketamine binding to ai‐adrenoceptors. Displacement studies of [125I]‐CYP by ketamine showed a Kd of 0.35±0.03× 10−3 mol/L for ketamine binding to β2‐adrenoceptors.

4. We conclude that ketamine interacts directly with both ai‐ an. β2‐adrenoceptors and that such interactions probably explain the reported effects of this agent on the vasculature and the bronchial tree.
RAPID REVERSAL OF ENDOTHELIAL DYSFUNCTION IN HYPERCHOLESTEROLAEMIC RABBITS TREATED WITH SIMVASTATIN AND PRAVASTATIN
Authors: Jorge Paulo A Ribeiro , Osaki Michiko R. , de Almeida Eros
Published: June 2007

1. The main objective of the present study was to verify the speed with which two 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, simvastatin and pravastatin, could revert endothelial cell dysfunction in hypercholesterolaemic rabbits. An attempt was also made to correlate the plasma cholesterol level and the tissue cholesterol and malondialdehyde (MDA) contents of the aortae with the endothelium‐dependent relaxation on the assumption that any endothelial dysfunction could be rapidly and partially reversed, even in the presence of relatively high serum cholesterol levels.

2. Ninety‐one male New Zealand white rabbits were randomly assigned to hypercholesterolaemic (control), simvastatin or pravastatin groups. All rabbits were fed a diet supplemented with cholesterol (0.5%) and coconut oil (2%) for 8 weeks. Simvastatin (10 and 20 mg/day) and pravastatin (15 and 30 mg/day) were administered 6, 4 and 2 days before the end of the experiment. At the end of the 8th week, animals were killed and the aortae were removed for histological examination as well as for the measurement of cholesterol and MDA contents and for endothelium‐dependent relaxation studies.

3. The results showed that significant improvement in endothelium‐dependent relaxation was obtained only with pravastatin and only with 4 or 6 days of administration. In these cases, the cholesterol and MDA contents of the vessel wall were reduced, although no significant changes were observed in plasma total cholesterol. Higher doses of the drugs did not alter these results.

4. We conclude that pravastatin enhances endothelium‐dependent relaxation when administered to cholesterol‐fed rabbits, probably via an anti‐oxidant action. This effect, which was observed to start on the 4th day of drug administration, may represent a new therapeutic approach for the treatment of acute coronary syndromes in hypercholesterolaemic patients.
EXTRACTS OF GINKGO BILOBA AND GINSENOSIDES EXERT CEREBRAL VASORELAXATION VIA A NITRIC OXIDE PATHWAY
Authors: Chen X , Salwinski S , Lee TJ‐F
Published: June 2007

1. Extracts from the leaves of Ginkgo biloba (EGb) and ginsenosides (GS) have been reported to be effective at increasing vascular relaxation. In the present study, the actions of EGb and GS on the vascular functions of porcine basilar arteries were investigated in vitro using tissue bath techniques.

2. Both EGb and GS relaxed the basilar artery in a concentration‐dependent and partly endothelium‐dependent manner. However, EGb appeared to be more potent than GS. Relaxation induced by transmural nerve stimulation (TNS) was significantly enhanced by EGb (7.5, 15 and 30 μg/mL) and GS (20, 40 and 80 μg/mL| in both endothelium‐intact and ‐denuded basilar arteries. Enhanced TNS‐induced relaxations were abolished by 0.3 mmol/L N‐h ‐arginine.

3. The present study demonstrates that nitric oxide plays a primary role in TNS‐induced relaxation as well as in EGb‐ and GS‐enhanced relaxation within the cerebral vasculature. In addition, our data support the potential of these compounds as therapeutic strategies in cerebral ischaemia and other related vascular dysfunctions.
ENDOTHELIUM‐SMOOTH MUSCLE INTERACTIONS IN BLOOD VESSELS
Authors: van Breemen Cornells , Skarsgard Peter , Laher Issy , McManus Bruce , Wang Xiaodong
Published: June 2007

1. Blood vessel tone is determined both by smooth muscle and endothelial functions. In coronary arteries taken from rat (Fisher‐Lewis) cardiac transplanted hearts, the inducible form of NOS (iNOS) in smooth muscle is more active, while acetylcholine‐induced nitric oxide production in the endothelium is greatly diminished. This causes a greatly reduced myogenic constriction, in pressurized septal arteries taken from immunologically challenged transplanted hearts.

2. The sarcoplasmic reticulum (SR) of smooth muscle and the endoplasmic reticulum (ER) of endothelial cells sequeste. Ca2+ from the cytoplasm. This reduces the intracellular concentration of free Ca2+, which is necessary for the activation of cellular processes. The release of Ca2+ from internal stores occurs through ryanodine and IP3 recoptors located on the SR membrane.

3. The superficial SR/ER also interacts with ion exchangers and pumps in the plasma membrane. This allows for the superficial SR/ER to function in Ca2+ extrusion; for example, inhibition of the SR/ER Ca2+‐ATPase (SERCA) partially inhibits the rate of loss Ca2+ from the cell. Recent data suggest that the SR Ca2+‐ATPase and the Na+‐Ca2+ exchanger of smooth muscle cells function in series; that is, Ca2+ uptake by the SR followed by release towards the exchanger to mediate extrusion. This interaction between the SERCA of the superficial SR and ion exchangers and pumps creates intracellular Ca2+ gradients.

4. The SERCA of the superficial, peripherally distributed SR/ER also serves to regulat. Ca2+ entry from the extracellular space. This occurs in part by inhibition of the superficial buffer barrier function of the SR as well as by depletion of stimulated Ca2+ entry.

5. Ca2+ entry is also regulated in endothelial and smooth muscle cells by the membrane potential. Membrane hyperpolar‐ization increases the driving force for Ca2+ entry into endothelial cells, which lack voltage‐gated Ca2+ channels, and reduces open ate probability of voltage‐gated Ca2+ channels in vascular smooth muscle cells. The two cell types have electrical contact and interact in a dynamic manner to regulate blood vessel diameter
ABNORMAL KIDNEY FUNCTION AS A CAUSE AND A CONSEQUENCE OF OBESITY HYPERTENSION
Authors: Hall John E. , Brands Michael W. , Henegar Jeffrey R. , Shek Eugene W.
Published: June 2007

1. Obesity is the most common nutritional disorder in the US and is a major cause of human essential hypertension. Although the precise mechanisms by which obesity raises blood pressure (BP) are not fully understood, there is clear evidence that abnormal kidney function plays a key role in obesity hypertension.

2. Obesity increases tubular reabsorption and this shifts pressure natriuresis towards higher BP. The increased tubular re‐absorption is not directly related to hyperinsulinaemia, but is closely linked to activation of the sympathetic and renin‐angiotensin systems, and possible changes in intrarenal physical forces caused by medullary compression due to accumulation of adipose tissue around the kidney and increased extracellular matrix within the kidney.

3. Obesity is also associated with marked renal vasodilation and increased glomerular filtration rate, which are compensatory responses that help overcome the increased tubular re‐absorption and maintain sodium balance. However, chronic renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli which, along with increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. Because obesity is a primary cause of essential hypertension as well as type II diabetes, there is good reason to believe that obesity may also be the most frequent cause of end‐stage renal disease.

4. Future research is needed to determine the mechanisms by which excess weight gain activates the neurohumoral systems and alters renal structure and function. Because of the high prevalence of obesity in most industrialized countries, unravelling these mechanisms will likely provide a better understanding of the pathophysiology of human essential hypertension and chronic renal failure.
DRIVING RESPIRATION: THE RESPIRATORY CENTRAL PATTERN GENERATOR
Authors: Bellingham Mark C.
Published: June 2007

1. The central pattern generator (CPG) for respiration is located in the brainstem and produces rhythmic synaptic drive for motoneurons controlling respiratory muscles. Based on respiratory nerve discharge, the respiratory cycle can be divided into three phases: inspiration, postinspiration and stage 2 expiration.

2. Six basic types of respiratory neuron participate in respiratory rhythmogenesis. Their firing and membrane potential patterns are locked to different phases of the respiratory cycle.

3. In adult mammals, respiratory neurons are subject to excitatory and inhibitory synaptic inputs and show extensive synaptic interconnections that are mainly inhibitory. There are differences in the relative importance of excitatory and inhibitory synaptic drives and the neurotransmitters involved in respiratory rhythmogenesis in neonates compared with adults.

4. Respiratory neurons possess a number of intrinsic membrane currents that may be involved in central pattern generation, including low‐ and high‐voltage‐activated calcium, potassium, calcium‐dependent potassium, sodium and mixed cationic currents. More quantitative information is needed about the distribution and characteristics of these ionic currents if we are to understand rhythmogenesis.

5. The two main theories for the origin of respiratory rhythm are those of pacemaker neuron‐driven and synaptic network‐driven CPG. Evidence derived from in vivo and in vitro experiments exists to support both of these theories. There may be a significant switch in the underlying mechanism driving the respiratory CPG during postnatal development.
AUTOINHIBITION, SYMPATHETIC COTRANSMISSION AND BIPHASIC CONTRACTILE RESPONSES TO TRAINS OF NERVE STIMULATION IN THE RODENT VAS DEFERENS
Authors: Ventura Sabatino
Published: June 2007

1. The present review critically discusses the evidence for and against the various hypotheses that have been proposed to explain the biphasic contractile response of the rodent vas deferens to trains of electrical field stimulation (EFS).

2. It is widely accepted that the initial component of the biphasic response of the rodent isolated vas deferens to trains of EFS is mediated by ATP and the second slower tonic contraction is mediated by noradrenaline (NA). This theory is based on the ability of antagonists of the post‐junctional receptors for these neurotransmitters to inhibit the respective components of the biphasic response and on the ability of exogenous application of either ATP or NA to mimic the responses of each phase.

3. Prejunctional autoinhibition has also been proposed as the cause of the biphasic response. This is based primarily on the ability of α2‐adrenoceptor antagonists to transform responses from biphasic to monophasic and on the ability of neuronal NA uptake inhibitors to accentuate the separation of the two phases.

4. Atypical or extrajunctional NA receptors have also been proposed to be the mediators of the component of the response to nerve stimulation that is resistant to the traditional α‐adrenoceptor antagonists.

5. Different contractile mechanisms and/or sources of calcium have also been postulated to cause the biphasic response. Blockers of intracellular Ca2+ mobilization are able to block the initial component, while blockers of extracellular Ca2+ entry inhibit the second tonic phase.

6. It is concluded that because α1‐adrenoceptor antagonists and blockers of P2 purinoceptors have also been shown to block both phases of the response to trains of EFS, prejunctional auto‐inhibitory mechanisms perhaps provide the most sound explanation for the phenomenon of the biphasic contractile response to trains of EFS.
NEUTRAL ENDOPEPTIDASE 3.4.24.11 INHIBITION POTENTIATES THE INHIBITORY EFFECTS OF TYPE‐C NATRIURETIC PEPTIDE ON LEUKOTRIENE D4‐INDUCED AIRWAY CHANGES
Authors: Ohbayashi Hiroyuki , Yamaki Kenichi , Suzuki Ryujiro , Kume Hiroaki , Takagi Kenzo
Published: June 2007

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type‐C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4 ‐induced airway microvascular leakage and bronchocon‐striction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor.

2. Anaesthetized male guinea‐pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 μg/kg LTD4 and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage.

3. Intravenous administration of CNP (100, 300 and 1000 μg/kg) significantly inhibited the LTD4‐induced microvascular leakage and bronchoconstriction in a dose‐dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP.

4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.
MECHANISMS OF INSULIN RESISTANCE AND NEW PHARMACOLOGICAL APPROACHES TO METABOLISM AND DIABETIC COMPLICATIONS
Authors: Donnelly Richard , Qu Xianqin
Published: June 2007

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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.
AGE‐RELATED CHANGES IN AORTIC SENSITIVITY TO NORADRENALINE AND ACETYLCHOLINE IN RATS
Authors: Hashimoto Michio , Gamoh Shuji , Hossain Shahdat , Okunishi Hideki , Shimoura Keiko , Yasui Yukihiko , Ando Akiro , Masumura Sumio
Published: June 2007

1. The purpose of the present study was to determine the relationship between plasma and tissue lipid levels and the effects of age on vascular responses to noradrenaline (NA) and acetylcholine (ACh).

2. Studies were performed in young and aged rats and the response of endothelium‐intact and ‐denuded aortic rings to NA and to ACh was measured. The plasma concentration of cholesterol (total, high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL)) and 17β‐oestradiol was determined, as was the aortic tissue content of phospholipids, cGMP and cholesterol (total, free and esterified).

3. Levels of all types of cholesterol in plasma and aorta increased with age; cholesterol levels in plasma correlated with those in the aorta; levels of phospholipid in the aorta did not increase with age but correlated with those of LDL cholesterol in plasma; levels of 17β‐oestradiol did not change, but those of cGMP increased with age.

4. In endothelium‐intact rings, the maximum tension developed by exposure to NA did not change, but the EC50 of NA increased with age and correlated with total cholesterol in the plasma and with the levels of all types of cholesterol in the aorta. In rings precontracted with NA, age decreased the maximum relaxation induced by ACh. The EC50 of ACh decreased with age and was inversely correlated with levels of cholesterol in the plasma and aorta. Treatment with NA increased cGMP levels in aged rats. Removal of the endothelium abolished the response to ACh and heightened the sensitivity to NA in young and aged rats.

5. Aortic endothelial cells seem to inhibit amine‐induced contraction, while age‐related changes in the levels of cholesterol in aortic tissue affect the sensitivity of the tissue to NA and ACh.
MOBILIZATION OF LEAD BY CALCIUM VERSENATE AND DIMERCAPTOSUCCINATE IN THE RAT
Authors: Tandon Sushil K. , Singh Surendra , Prasad Satgur , Mathur Neeraj
Published: June 2007

1. Calcium disodium ethylenediaminetetraacetate (CaNa2 EDTA) and meso‐2,3‐dimercaptosuccinic acid (DMSA) individually and in permutation‐combination in various doses (0.1,0.2 and 0.4 mmol/kg bodyweight) were investigated for their efficacy to mobilize lead from vital tissues into urine and faeces and to restore the lead‐sensitive biochemical parameters in lead pre‐exposed rats with a view to develop the most acceptable treatment regimen for lead poisoning with a minimal loss of endogenous essential elements.

2. The combined therapy was more effective than a single chelator treatment.

3. The combination of 0.2 mmol/kg CaNa2EDTA + 0.4 mmol/kg DMSA caused a lower depletion of zinc, calcium and iron but possessed almost equal capability to that of 0.4 mmol/kg CaNa2EDTA + 0.4 mmol/kg DMSA to produce urinary as well as faecal excretion of lead, to reduce the tissue burden of lead, including that of the brain, and to reverse lead‐induced biochemical alterations.

4. The combination of 0.2 mmol/kg CaNa2EDTA + 0.4 mmol/kg DMSA has shown a definite improvement over previously reported combinations in terms of removal of lead from tissues, particularly the brain, restoration of urinary delta‐aminolevulinic acid levels and a decrease in the loss of body zinc and is, therefore, recommended for the treatment of lead intoxication.
LATE STEPS OF ALDOSTERONE BIOSYNTHESIS: SHEEP ARE NOT RATS
Authors: Boon Wah Chin , Coghlan John P. , McDougall John G.
Published: June 2007

1. The last three steps of aldosterone biosynthesis have been demonstrated to be catalysed by a single enzyme, referred to as CYP11B (or P45011β) in cow, pig, sheep and bullfrog and as CYP11B2 (or P450aldo) in rat, human, mouse and hamster.

2. The related enzyme CYP11B1 (also referred to as P45011β) in rat, human, mouse and hamster does not have aldosterone synthesis activity, but no such enzyme has been reported in the cow, pig or sheep to date.

3. Exclusive aldosterone secretion in the zona glomerulosa (ZG) of the adrenal cortex in species such as rat, human, mouse and hamster could be ascribed to the restricted distribution of CYP11B2 to the same region in the adrenal cortex.

4. In other species, such as cow, pig and sheep, the CYP11B enzyme is expressed throughout the adrenal cortex and, thus, the exclusive aldosterone biosynthesis in the ZG could not be explained simply by the distribution of the enzyme.

5. We have shown in the sheep that potassium loading and acute sodium depletion stimulate the CYP11B transcript levels, which are not further increased by chronic sodium depletion.

6. The predominant CYP11B in the sheep adrenal cortex catalyses the synthesis of aldosterone from deoxycorticosterone (DOC) in vitro, is expressed throughout the adrenal cortex and the corresponding transcript levels are increased by K+ loading or sodium depletion. In short, as far as the last step of aldosterone biosynthesis is concerned, sheep are different from rats. In the rat, the CYP11B2 transcript or protein is elevated by K+ loading or sodium depletion, but not the CYP11B1 transcript or protein.

7. We propose that during severe sodium deficiency there is a switch in the aldosterone pathway to one preferentially involving 18‐OH‐DOC and not corticosterone.
NITRIC OXIDE IN ATHEROSCLEROSIS: VASCULAR PROTECTOR OR VILLAIN?
Authors: Dusting Gregory J. , Fennessy Paul , Yin Zhan‐Li , Gurevich Vladimir
Published: June 2007

1. Nitric oxide (NO) has important roles in physiological vasodilatation, cytotoxicity and vascular disease. Nitric oxide and prostacyclin (PGI2), both released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they synergize in terms of vasodilatation.

2. The development of atherosclerosis and hyperlipaemia per se is accompanied by impairment of endothelium‐dependent vasodilatation.

3. Atherosclerosis is associated with marked changes in the activity of isoforms of NO synthase (NOS) in the artery wall, including increased expression of the NOS2 (inducible) isoform in complex human lesions as well as in the neointima of experimental animal models.

4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions propitious for leucocyte adhesion, vasospasm, thrombosis and, in addition, may promote increased proliferation of intimal cells.

5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclerosis react to form cytodestructive per‐oxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a factor in apoptosis of cells leading to plaque rupture.

6. We have been able to reverse these NO defects with therapeutic agents, including angiotensin‐converting enzyme inhibitors, antagonists of platelet‐activating factor and NO donor compounds, all offering promise in protecting against some manifestations of vascular disease.
NATRIURESIS AND INHIBITION OF Na+/K+‐ATPase: MODULATION OF RESPONSE BY PHYSIOLOGICAL MANIPULATION
Authors: McDougall John G. , Yates Neale A.
Published: June 2007

1. There is considerable evidence for the existence of an endogenous inhibitor of Na+/K+‐ATPase. The exact physiological nature and role of this postulated agent remains unclear although it would be predicted that one of its actions would bi stimulation of renal sodium excretion.

2. The natriuretic effect of renal arterial infusion of ouabain is relatively slow in onset and is sustained.

3. The natriuresis is not modified by changes in sodium status unlike the natriuretic effect of atrial natriuretic peptide.

4. The natriuretic action of ouabain is enhanced dramatically by acute volume expansion or chronic mineralocorticoid treatment, which both result in hypokalemia, hypertension am hypervolemia.

5. The natriuretic response to small increments in blood pressure is markedly enhanced by treatment with ouabain.

6. We hypothesize that the interaction between the inhibition of Na+/K+‐ATPase and elevated blood pressure could result in the shedding of sodium in conditions where there are increased levels of circulating endogenous digitalis‐like factors.