bluuebunny/crossref_metadata_2025 huggingface dataset:
INFLUENCE OF MUSCLE BLOOD FLOW ON FATIGUE DURING INTERMITTENT HUMAN HAND‐GRIP EXERCISE AND RECOVERY
Authors: Pitcher Julia B. , Miles Timothy S.
Published: June 2007

1. The influence of muscle blood flow on fatigue and recovery was studied in the forearm muscles of eight male subjects performing a powerful isometric hand‐grip exercise. The exercise was performed with the exercising forearm normally perfused and, on a separate occasion, with its blood flow occluded with a sphygmomanometer cuff.

2. In the no cuff condition, peak force declined to an initial plateau at 40–50% of the maximal voluntary grip force (MVC). When perfusion was occluded, the force decline was similar during the first minute of exercise, then force fell rapidly to exhaustion.

3. In a separate experiment to investigate the mechanisms underlying the plateau in force loss, occlusion of blood flow during the force plateau phase resulted in a rapid decline in force to exhaustion.

4. Recovery of peak force after the cuff exercise was significantly greater during the initial 3.5 min of recovery than after no‐cuff exercise. After this time, recovery was similar for both conditions.

5. Muscle blood flow occlusion during intermittent exercise profoundly reduces endurance without prolonging recovery. Recovery time may depend on the duration and energy cost of the exercise rather than on the degree of force loss.

6. The present study suggests that the fall in muscle force induced by a continuous MVC is a combination of profound short‐term fatigue in anaerobic muscle fibres due to the consumption of their short‐term energy supplies, plus a decline in force production by aerobic muscle fibres that is the consequence of hypoxia. Thus, MVC may not be a good model of fatigue occurring under submaximal conditions, as hypoxia of type I fibres is unlikely to occur under physiological conditions in which muscle contractions are usually intermittent.
COMPONENTS OF THE BLOOD ACID‐BASE DISTURBANCE THAT ACCOMPANIES URETHANE ANAESTHESIA IN RATS DURING NORMOTHERMIA AND HYPOTHERMIA
Authors: Alfaro V. , Palacios L.
Published: June 2007

1. We have studied the components of the metabolic acidosis that accompanies urethane anaesthesia in rats, both with and without the hypothermia that results from this anaesthesia.

2. Acid‐base disturbances were analysed with an approach based on Stewart's analysis of acid‐base chemistry.

3. The pH fall in the blood of normothermic anaesthetized rats (body temperature Tb) = 37°C) was related to increases in plasma anions (lactate and [Cl−]), which decreased the strong ion difference ([SID]), as well as to increase the weak acid buffers due to increases in albumin.

4. A stronger metabolic acidosis was found in the blood of rats with hypothermia induced by urethane (Tb= 32°C). Although plasma lactate was unchanged in hypothermic rats, [SID] decreased due to alterations in the plasma ionic balance. The metabolic acidosis found in hypothermia was also associated with increased weak acid buffers due to increases in albumin and inorganic phosphate. Further to hyperphosphataemia, signs of acute renal disfunction, such as increases in plasma [Mg2+] and blood urea nitrogen were found. Plasma retention of endogenous acids together with the retention of acid end‐products of the metabolism of urethane because of acute renal failure may have contributed to strengthening the fall in pH and [HCO3−] found in urethane‐induced hypothermic rats.
MEMBRANE AND SECRETORY PROPERTIES OF RENAL JUXTAGLOMERULAR GRANULAR CELLS
Authors: Kurtz Armin
Published: June 2007

1. The control of renin secretion from renal juxtaglomerular granular cells on the cellular level is not yet completely understood.

2. There is evidence that calcium‐ and cyclic nucleotide‐related pathways exert an opposite control of renin secretion.

3. There is accumulating evidence that the electrical properties of juxtaglomerular cells are important for the regulation of renin secretion.
PHARMACOLOGICAL ACTION OF AUSTRALIAN ANIMAL VENOMS
Authors: Hodgson Wayne C.
Published: June 2007

1. Australia has some of the most venomous fauna in the world. Although humans are not usually perceived as being predators against these animals they are often envenomated, accidentally or otherwise. This has led to the development of antivenoms against some of the potentially lethal venoms. However, further understanding of the mechanism(s) of action of these and other venoms is important, not only for developing new treatment strategies but also in the search for novel research tools.

2. The present review discusses the pharmacology of some of the components found in venoms and outlines the research undertaken on some of Australia's venomous animals, with the exception of snakes.

3. Biogenic amines, peptides and enzymes are common venom components and produce a wide range of effects in envenomated humans. For example, respiratory failure observed after envenomation by the box jellyfish (Chironex fleckeri) and Sydney funnel‐web spider (Atrax robustus) is most likely due to potent neurotoxins in the venoms. Stonefish (Synanceja trachynis) and platypus (Ornithorhynchus anatinus) venoms, although not considered lethal, cause severe pain. However, the components responsible for these effects have not been isolated. Venom components, as yet unidentified, may be responsible for the cutaneous necrotic lesions that have been reported after some spider bites (e.g. Lampona cylindrata). Other venoms, such as those of the jumper ant (Myrmecia pilosula) and bull ant (M. pyriformis), may produce only mild skin irritation to the majority of humans but a severe anaphylactic response in sensitized victims.

4. While there has been a renewed interest in toxinology, further research is required to fully elucidate the pharmacological action of many of these venoms.
DIFFERENTIAL REGULATION OF NATRIURETIC PEPTIDE GENES IN INFARCTED RAT HEARTS
Authors: Shimoike Hitoshi , Iwai Naoharu , Kinoshita Masahiko
Published: June 2007

1. We investigated the regulation of the atrial natriuretic peptide and brain natriuretic peptide genes in a rat model of myocardial infarction induced by isoproterenol (IP rat) and in a rat model of cardiac hypertrophy induced by aorto‐caval shunt (AC shunt rat).

2. Brain natriuretic peptide (BNP) mRNA levels in atria were significantly higher in IP rats than in controls at 18 h after the administration of isoproterenol, but no significant increases were observed in atrial natriuretic peptide (ANP) mRNA expression levels at any time point examined. In the ventricles, the BNP mRNA levels peaked at 18 h after isoproterenol administration, whereas ANP mRNA levels gradually increased until 3 days after isoproterenol administration.

3. The BNP mRNA levels in both atria and ventricles were significantly increased at 1 day after the introduction of aorto‐caval shunt, while the ANP mRNA levels were not.

4. Plasma BNP levels were closely correlated with left ventricular weight per bodyweight, in both IP rats and AC shunt rats.

5. These results suggest the differential regulation of ANP and BNP genes in both the atria and ventricles in these two pathological models.
THE SYMPATHETIC NERVOUS SYSTEM AND LONG‐TERM REGULATION OF ARTERIAL PRESSURE: WHAT ARE THE CRITICAL QUESTIONS?
Authors: Osborn John W.
Published: June 2007

1. The role of the sympathetic nervous system in long‐term control of arterial pressure remains unclear despite decades of intense research.

2. Previous studies have shown that denervation of arterial baroreceptors does not chronically increase arterial pressure. As baroreceptors are thought to provide the primary ‘error signal’ to the autonomic nervous system, this has been interpreted as evidence against neural control of arterial pressure over long periods of time.

3. The possibility that other ‘error signals’ are important in the long‐term control of sympathetic activity (and arterial pressure) is introduced.

4. The following ‘Critical Questions’ are presented for subsequent discussion: (i) is the sympathetic nervous system a ‘major player’ in the long‐term control of arterial pressure; (ii) why doesn't arterial pressure remain at hypertensive levels after arterial baroreceptor denervation; and (iii) which ‘error signals’ are most important in the long‐term control of sympathetic outflow?
INTERACTIONS BETWEEN VASOPRESSIN AND BAROREFLEX CONTROL OF THE SYMPATHETIC NERVOUS SYSTEM
Authors: Hasser Eileen M. , Bishop Vernon S. , Hay Meredith
Published: June 2007

1. In addition to its effects at the renal tubules to influence water retention and at vascular smooth muscle to cause vasoconstriction, the hormone arginine vasopressin also appears to modulate cardiovascular reflex control of the sympathetic nervous system. Infusion or endogenous release of vasopressin results in enhanced baroreflex sympatho‐inhibitory responses compared with other pressor agents. In addition, when changes in arterial pressure are imposed on an elevated background level of circulating vasopressin, due either to infusion or endogenous release, the arterial baroreflex response is shifted to lower pressures, and the maximum sympatho‐excitation to a decrease in pressure is reduced.

2. Evidence suggests that vasopressin may influence cardiovascular reflex function at multiple sites. Nevertheless, the primary site involved in the effects of circulating vasopressin on baroreflex function appears to be in the central nervous system, specifically in the area postrema. Lesion of the area postrema abolishes the ability of circulating vasopressin to modulate arterial baroreflex and cardiopulmonary reflex function and electrical or chemical stimulation of this circum‐ventricular organ mimics the effects of vasopressin. In addition, vasopressin has been shown to influence the activity of area postrema neurons in vivo and in vitro. Although not all studies agree, the effects of the area postrema and vasopressin on cardiovascular reflex function appear to be dependent on afferent input from peripheral baroreceptors.

3. Most evidence suggests that vasopressin exerts its effects on baroreflex function through a V1 vasopressin receptor mechanism. Systemic administration or microinjection into the area postrema of a specific V1 receptor antagonist abolishes the action of arginine vasopressin on arterial baroreflex and cardiopulmonary reflex control of the sympathetic nervous system.

4. The ability of vasopressin and the area postrema to influence baroreflex function appears to be dependent on an α2‐adrenoceptor mechanism at the level of the nucleus tractus solitarius (NTS). Blockade of α2‐adrenoceptors in the NTS abolishes the effects of vasopressin and the area postrema on the sympathetic nervous system. Facilitation of NTS processing of baroreceptor afferent inputs by the area postrema could contribute to the enhanced sympatho‐inhibition and shift of the baroreflex curve to lower pressures during elevations in circulating vasopressin.
NEURAL CONTROL OF MUSCLE BLOOD FLOW: IMPORTANCE DURING DYNAMIC EXERCISE
Authors: Rowell Loring B.
Published: June 2007

1. The present review examines the control of muscle vascular conductance by the sympathetic nervous system during exercise.

2. Evidence for tonic sympathetic neural control of active muscle rests on three findings: (i) directly measured muscle sympathetic nerve traffic is increased; (ii) spillover of noradrenaline from active muscles is also increased; and (iii) withdrawal of sympathetic outflow to active muscle either by acute blockade of its sympathetic nerve supply or by reflex inhibition of sympathetic nervous activity raises muscle vascular conductance via inhibition of tonic vasoconstriction.

3. Loss of tonic sympathetic control of muscle vascular conductance during mild to severe exercise causes marked hypotension despite maintenance of a normal cardiac output.

4. The extent to which active muscle can vasodilate in intact animals appears to have been hidden by tonic vasoconstriction. This vasoconstriction appears to be minimally affected by metabolites in oxidative (red) muscle, but may be inhibited in predominantly glycolytic (white) muscle owing to different spatial distributions of α‐ and α2‐adrenoceptors in the two muscle types and to the different susceptibilities of the two receptor types to interference by metabolites.

5. The reflexes causing vasoconstriction in active and inactive muscles are unknown. One hypothesis is that a flow‐sensitive muscle chemoreflex raises sympathetic outflow to reduce accumulations of muscle metabolites caused by mismatches between muscle blood flow and metabolism, called ‘flow errors’. Another hypothesis is that the arterial baroreflex corrects mismatches between cardiac output and vascular conductance called ‘pressure errors’. This review argues for a dominance of control by the baroreflex based on the following observations: (i) the arterial baroreflex is essential to the normal rise in sympathetic nervous activity and arterial pressure at the onset of exercise; (ii) during submaximal exercise, a functioning arterial baroreflex is required to maintain tonic sympathetic activity and prevent arterial hypotension; and (iii) whereas a muscle chemoreflex may be needed to guard against hypoperfusion of active muscle, the arterial baroreflex must oppose hypotension by initiating sympathetic vasoconstriction to oppose muscle vasodilation.
HYPOTENSIVE EFFECT OF CHRONICALLY INFUSED ADRENOMEDULLIN IN CONSCIOUS WISTAR‐KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Khan Azharul Islam , Kato Johji , Kitamura Kazuo , Kangawa Kenji , Eto Tanenao
Published: June 2007

1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined in normotensive Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).

2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps. Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na+ and K+ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion.

3. A significant reduction in SBP was observed in hAM‐treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM‐treated WKY rats was found to be significantly lower than in control WKY rats during infusion. However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na+ excretion in hAM‐treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.0 ± 9.4 and 0.6 ± 0.2 fmol/mL, respectively.

4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit.
AUSTRALIAN COMPARATIVE OUTCOME TRIAL OF ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR‐ AND DIURETIC‐BASED TREATMENT OF HYPERTENSION IN THE ELDERLY (ANBP2): OBJECTIVES PROTOCOL
Authors: Reid C. M.
Published: June 2007

1. ANBP2 is a comparative outcome trial of angiotensin‐converting enzyme inhibitor‐ and diuretic‐based treatment of hypertension in the elderly using a prospective randomized open‐label design with blinding of endpoint assessments.

2. The primary objective is to determine, in hypertensive subjects 65–84 years of age, whether there is any difference in total cardiovascular events (fatal and non‐fatal) over a 5 year treatment period between the two treatment regimens.

3. The study is being conducted in general practices throughout Australia and will recruit 6000 subjects over 2–3 years (3000 in each arm of the study) to provide 30000 years of patient observation. This will allow detection of a 25% difference in the primary outcome variable at the 5% level with a power of 90%.

4. Following randomization to one of the treatment arms, each subject's blood pressure (BP) is managed by the general practitioner according to his/her usual practice to achieve goal BP with guidelines for drug therapy relevant to each treatment arm.

5. Study endpoint information is gained from a review of practice records every 3 months and these data are then assessed by an Endpoint Committee blinded for treatment randomization.

6. Interim analyses of endpoint data will be conducted at the end of randomization and then annually until the final analysis after 5 years of observation in each subject.
MECHANISM OF THE POTENTIATION OF VASOCONSTRICTION BY NEUROPEPTIDE Y IN ARTERIOLES FROM THE SUBMUCOSA OF THE GUINEA‐PIG SMALL INTESTINE
Authors: Neild TO , Xia J.
Published: June 2007

1. Neuropeptide Y (NPY; 3–100 nmol/L) caused a concentration‐dependent potentiation of constriction in response to noradrenaline or the thromboxane mimetic U46619 in arterioles from the submucosa of the guinea‐pig small intestine.

2. In arterioles permeabilized by exposure to the α‐toxin of Staphylococcus aureus and maintained in Ca2+‐buff'ered medium, NPY potentiated the contractile effects of Ca2+. The magnitude of the potentiation was the same as in intact arterioles.

3. Exposure of arterioles to 1 μmol/L nifedipine to inhibit Ca2+influx or to 20 μmol/L cyclopiazonic acid to abolish Ca2+ uptake into internal stores had no effect on the potentiating action of NPY.
PAPAVERIVE ABOLISHES ENDOTHELIUM‐DEPENDENT DILATATION OF HUMAN INTERNAL MAMMARY ARTERIES IN VITRO
Authors: Schyvens Christopher G. , Owe‐Young Robert A. , Spratt Philip M. , Mundy Julie A. , Farnsworth Alan E. , Macdonald Peter S.
Published: June 2007

1. The purpose of the present study was to examine the effects of papaverine‐HCl, administered into the lumen of the human internal mammary artery (IMA) during harvesting of this vessel, on vascular reactivity in vitro and to specifically test the hypothesis that intraluminal administration of papaverine‐HCl impairs endothelium‐dependent vasodilation.

2. The present study measured in vitro dilator and constrictor responses of terminal segments of human IMA. Internal mammary artery segments were obtained either prior to routine administration of intraluminal papaverine (pre‐P) or after papaverine administration (post‐P) in patients undergoing coronary artery bypass grafting. In addition, the viability of cultured human saphenous vein endothelial cells exposed to papaverine‐HCl was examined.

3. Cumulative concentrations of U46619, 5‐hydroxytryptamine and phenylephrine (PE) produced active contractions in post‐P IMA rings. Contractile responses to low concentrations of endothelin‐1 were significantly enhanced in post‐P IMA compared with pre‐P IMA segments.

4. Maximal endothelium‐dependent vasodilator responses of pre‐P IMA segments to cumulative concentrations of acetylcholine (ACh) and the calcium ionophore A23187 were 49 ± 7 and 66 ± 4%, respectively, of the initial active tension induced by PE (1 umol/L).

5. Maximal endothelium‐dependent vasodilator responses were markedly attenuated in post‐P EVIA (6 ± 6 and 11 ± 10% for ACh and A23187, respectively; P 0.0001 for both vasodilators compared with pre‐P). Post‐P EVIA relaxed completely to the endothelium‐independent vasodilator sodium nitroprusside.

6. Exposure of cultured human saphenous vein endothelial cells to papaverine‐HCl (1.2 and 12.0 mg/mL) for 1 h resulted in the reduced viability of these cells.

7. The loss of endothelium‐dependent relaxation could dangerously predispose the IMA graft to vasospasm in the postoperative period.
BAROREFLEX CONTROL OF HEART RATE DURING HYPOXIA AND HYPERCAPNIA IN CHRONICALLY HYPERTENSIVE RABBITS
Authors: Groom Andrew S. , Malpas Simon C.
Published: June 2007

1. It has been proposed that hypertension alters the respiratory and cardiovascular responses to chemoreceptor stimulation. However, in studies of human hypertension or in genetic animal models of hypertension it has been difficult to unequivocally attribute the changes to hypertension per se, rather than to a genetic predisposition towards an altered chemoreflex response independent of hypertension.

2. In the present study a group of seven rabbits were made hypertensive via a continuous 7 week infusion of angiotensin II (Angll; 50 ng/kg per min, i.v.). Animals were studied twice before Angll treatment commenced, twice during infusion and 48 h after stopping infusion. At each of these times the relationship between heart rate (HR) and mean arterial pressure (MAP) was determined under normoxic, acute hypoxic (10% O2+ 3% CO2) and acute hypercapnic (18% O2+ 6.5% CO2) conditions for 20 min. A group of six animals also served as time controls.

3. Angiotensin II infusion increased arterial pressure from control levels of 80 ± 2 to 114 ± 8 mmHg and maintained it at this level throughout the 7 week period. After 1 week of Angll infusion there was a rightward shift in the heart rate‐baroreflex curve, indicating that the baroreflex was now operating at an increased level of pressure. These changes were associated with reductions in the gain from ‐7.6 ± 1.6 to—3.0 ± 0.2 b.p.m. /mmHg, HR range and curvature of the baroreflex. These effects were maintained throughout the 7 weeks of hypertension and were reversed within 2 days of ceasing Angll infusion. Acute hypoxia and hypercapnia in normotensive animals caused a reduction in the HR range of 19 ± 7 and 15 ± 7 b.p.m., respectively, but caused no change in the gain (sensitivity) of the baroreflex. Despite the marked changes in the baroreflex produced by the hypertension, the effect of hypoxia or hypercapnia on the HR baroreflex was not different in the hypertensive group.

4. It is concluded that chronic experimental AngII‐based hypertension does not alter the HR baroreflex response to hypoxia or hypercapnia and suggests that the altered responses seen in other studies is due to a genetic predisposition as opposed to the effect of raised arterial pressure.
ANTI‐AGEING EFFECT OF AGED GARLIC EXTRACT IN THE INBRED BRAIN ATROPHY MOUSE MODEL
Authors: Moriguchi Toru , Saito Hiroshi , Nishiyama Nobuyoshi
Published: June 2007

1. The effects of chronically administered aged garlic extract (AGE) on the age‐related changes in a novel strain of senescence accelerated mouse (SAM) characterized by age‐related brain atrophy (SAMP10) were investigated.

2. A solid diet containing 2% (w/w) AGE was given to SAM from 2 months of age.

3. The grading score of senescence in SAMP10 at 10 months of age was significantly higher than that of SAMR1, a reference strain for SAMP10.

4. Administration of AGE prevented the increase in the grading score of SAMP10 and SAMR1.

5. In behavioural evaluation, AGE improved learning and memory deficits of SAMP10 in both the passive and conditioned avoidance tests as well as the spatial memory test.

6. Treatment with AGE in SAMP10 prevented the decrease in brain weight and the atrophic changes in frontal brain at 12 months of age.

7. These results raise the possibility that AGE prevents physiological ageing and may be beneficial for age‐related cognitive disorders in humans.
PHYSIOLOGY OF AIRWAY NARROWING
Authors: Mitchell HW
Published: June 2007

1. Responsiveness of the bronchial tree is measured at the mouth in vivo and represents narrowing responses of multiple airways in the lung. Responsiveness of individual bronchi has not been adequately investigated and the dynamic changes associated with airway narrowing are largely undefined.

2. Responsiveness to cholinergic drugs was determined in bronchial segments in vitro, from lumen flow and narrowing, and from the force and shortening of the smooth muscle producing these responses.

3. Maximum flow reduction was produced by submaximum smooth muscle force and shortening. In 2 mm inner diameter bronchi, flow was abolished by acetylcholine but the lumen was not physically closed. Flow sensitivity was increased more in small diameter bronchi than in large, but this was not associated with differences in force by smooth muscle. Smooth muscle contraction increased the thickness of the total airway wall via a tensioning and expansion of mural elastic fibres. Flow responses were more sensitive to drugs placed adventitially than luminally.

4. Results define a major role for airway geometry and location, the epithelial barrier and the intercellular matrix, which couples the smooth muscle to the cartilaginous airway adventitia, in determining responsiveness of intact airways.
ROLE OF TACHYKININS IN BRONCHIAL HYPER‐RESPONSIVENESS
Authors: Reynolds Paul N. , Holmes Mark D. , Scicchitano Raffaele
Published: June 2007

1. Sensory afferent fibres mediate important protective reflexes in the lung. Small, unmyelinated C‐fibre nerves have both sensory afferent and effector functions. C‐fibres contain a number of neuropeptides, including the tachykinins, which have proinflammatory effects in the airways. Following stimulation with capsaicin and other stimuli, neuropeptides are released from the nerve endings, either directly or by axonal reflexes.

2. Important tachykinin effects include smooth muscle contraction, vasodilatation and oedema, mucus secretion and inflammatory cell activation. There are also trophic effects, including proliferation of fibroblasts, smooth muscle and epithelial cells.

3. Tachykinins mediate their effects by binding to G‐protein‐linked receptors. Receptor‐specific agonists and antagonists are available, which have helped clarify the effects of tachykinins. These agents may have therapeutic potential.

4. Tachykinins are degraded by the enzyme neutral endo‐peptidase.

5. Studies in humans in vivo show an increase in airways resistance following challenge with tachykinins. There is some evidence for an increase in tachykinins and their receptors in airway inflammation, but this has not been found in all studies. A reduction in neutral endopeptidase has been seen in some animal models of airway inflammation, but this has not been shown in human disease.

6. Trials of tachykinin receptor antagonists in human asthma have begun, but it is too early to say what their therapeutic impact will be.
USE OF GENE‐MANIPULATED MODELS TO STUDY THE PHYSIOLOGY OF LIPID TRANSPORT
Authors: Mortimer B‐C , Martins I. , Zeng BJ , Redgrave TG
Published: June 2007

1. In vivo and in vitro gene‐manipulated models were used to study the metabolism of chylomicron remnants. Transgenic mice expressing human apolipoprotein (Apo) A1 or E4, gene knockout mice deficient in ApoE or low density lipoprotein (LDL) receptors and antisense gene inhibition in HepG2 cells were used to evaluate the effect of gene manipulations on the metabolism of chylomicron remnants.

2. Mice transgenic for human ApoE4 showed accelerated clearance of chylomicron‐like emulsions when animals were fed a low‐fat diet. When challenged by a high‐fat diet, remnant clearance in ApoE4 transgenic mice was delayed, as in normal or non‐transgenic controls. However, unlike normal non‐transgenic controls, in ApoE4 transgenic mice high density lipoprotein (HDL)‐choIesterol levels remained high after high‐fat feeding, which probably protected the animals from the development of atherosclerosis.1 In contrast, clearance of chylomicron‐like lipid emulsions was not affected by the over‐expression of human ApoAI in transgenic mice.

3. Gene knock‐out mice deficient in ApoE or deficient in the LDL receptor were used to show that ApoE and LDL receptors are both essential for the normal, fast catabolism of chylomicron remnants by the liver.2 In the absence of the LDL receptor, an alternative ApoE‐dependent pathway operates to clear chylomicrons from the plasma, with significantly delayed catabolism.

4. Antisense gene inhibition techniques were used to suppress the expression of syndecan, a core protein of heparan sulfate proteoglycan, in HepG2 cells. Remnant uptake in cells transfected with the antisense oligodeoxynucleotide complementary to a 20 nucleotide sequence upstream of the initiation site of syndecan cDNA markedly reduced the uptake of chylomicron remnant.
UPDATE: MICROCOMPUTER STATISTICS PACKAGES. A PERSONAL VIEW
Authors: Ludbrook John
Published: June 2007

1. There have been a number of recent commercial developments and new versions of microcomputer statistical software packages since the last review in December 1995.

2. New versions for Windows have been released: SPSS 7.0 (Windows 95), SYSTAT 6.0 (Windows 3.11, 95, NT) and MINITAB 11.0 (Windows 3.11, 95, NT).

3. The minimum requirements of microcomputer hardware to run the statistical packages under Windows now include 486 or Pentium processors and 16 Mb of RAM.

4. It is now clear to the reviewer that no package that operates under Windows can be recommended unless it is possible to execute analyses by commands as well as by menus.

5. The Internet is an important medium for disseminating information about forthcoming new versions of statistical software packages and about flaws in recently released versions of such packages.
NEUROTROPHIC FACTORS ARE REQUIRED BY MATURE SYMPATHETIC NEURONS FOR SURVIVAL, TRANSMISSION AND CONNECTIVITY
Authors: Rush Robert A. , Chie Edward , Liu Dennis , Tafreshi Azita , Zettler Christian , Zhou Xin‐fu
Published: June 2007

1. Two neuronal growth factors, nerve growth factor (NGF) and neurotrophin 3 (NT3), have been studied for their action on the developing and mature sympathetic nervous system.

2. Antibodies to each factor have proved useful as reagents for the detection and quantification of NGF and NT3. They have also proved valuable in uncovering the functional roles of each factor by their ability to neutralize the endogenous molecules.

3. Nerve growth factor acts on postnatal neurons to control neurotransmission, connectivity and survival. Like NGF, NT3 is synthesized by effector tissues and is retrogradely transported by post‐ganglionic neurons to prevent cell death. However, the two factors have been shown to have quite distinct functions in mature neurons, indicating the existence of different signalling pathways. This differential action extends to secondary influences on satellite glia.

4. Pathological consequences result from excessive growth factor synthesis leading, in the hypertensive rat, to hyperinnerv‐ation and elevated blood pressure. Satellite glial cell synthesis of the factors and their receptors following peripheral nerve damage appears to be responsible for the establishment of inappropriate neuronal connections between sympathetic nerve terminals and sensory somata.

5. It is concluded that these potent factors control, by both coincident and independent mechanisms, sympathetic neuronal function throughout the life of the animal.
DETERMINANTS OF THE KINETICS OF VERY LOW‐DENSITY LIPOPROTEIN APOLIPOPROTEIN B‐100 IN NON‐OBESE MEN
Authors: Watts GF , Riches FM , Kelly JM , Powell MA , Croft KD
Published: June 2007

1. Apolipoprotein B‐100 (ApoB) is the principal structural and functional protein of the pro‐atherogenic lipoproteins. Elevated plasma apoB is an independent risk factor for coronary artery disease. In the present study we aimed to assess the factors that determine the kinetics of apoB in the very low‐density lipoprotein (VLDL) in healthy men.

2. We studied 17 non‐obese men who were consuming an ad libitum diet and had the following characteristics: mean (± SD) age 45.5 ± 9.7 years, body mass index (BMI) 25.1 ± 1.4 kg/m2, waist: hip ratio 0.91 ± 0.04, serum cholesterol 5.2 ± 0.6 mmol/L, triglycerides 1.08 ± 0.53 mmol/L and high‐density lipoprotein‐cholesterol 1.24 ± 0.31 mmol/L. Daily dietary intake was as follows: total fat 76 ± 26 g, carbohydrate 238 ± 67 g, protein 103 ± 33 g and alcohol 20 ± 16 g.

3. The kinetics of VLDL ApoB were studied using a primed, constant infusion (1 mg/kg per h) of l‐[13C]‐leucine over 8 h with measurement of isotopic enrichment of ApoB using gas chroma‐tography/mass spectrometry. The fractional turnover rate of VLDL ApoB was estimated using a monoexponential function. The mean (± SD) absolute hepatic secretion rate (ASR) of ApoB was 8.5 ± 4.6 mg/kg per day and the fractional catabolic rate (FCR) was 7.9 ± 5.6 pools/day. The ASR was significantly correlated with the waist: hip ratio (r= 0.60; P= 0.04), but not with age, BMI, weight or nutrient intake. The FCR was significantly and inversely correlated with plasma triglycerides (r =—0.53; P= 0.03) and alcohol intake (r = ‐0.48; P= 0.05).

4. In conclusion, the hepatic secretion of VLDL ApoB in non‐obese, healthy men is primarily determined by the waist: hip ratio, a measure of visceral fat. This is consistent with the hypothesis that the rate of lipid substrate supply to the liver regulates the output of ApoB. The fractional catabolism of VLDL ApoB may, however, be inversely related to alcohol intake and appears to determine the plasma concentration of triglycerides.
ACTIONS OF NITRIC OXIDE ON RENAL EPITHELIAL TRANSPORT
Authors: Stoos BA , Garvin JL
Published: June 2007

1. In vivo studies have demonstrated that nitric oxide (NO) induces natriuresis. Nitric oxide‐induced natriuresis occurs independently of changes in renal perfusion pressure, indicating that it is the result of a tubular effect of NO.

2. In support of this hypothesis investigators have shown that NO inhibits both Na+‐H+ exchange and Na+/K+‐ATPase activity in the proximal tubule. In the collecting duct, NO has been shown to decrease sodium flux with no effect on Na+/K+‐ATPase activity.

3. Thus, direct examination of the actions of NO have shown that NO can inhibit sodium transport in the nephron, which may account for the natriuresis observed in vivo.
PROTEIN KINASE C AND TRANSMITTER RELEASE
Authors: Majewski H. , Kotsonis P. , Iannazzo L. , Murphy TV , Musgrave IF
Published: June 2007

1. Protein kinase C (PKC) is an important second messenger‐activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca2+entry, presumably those involved in vesicle dynamics.

2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions.

3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high‐frequency stimulation and not during low‐frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca2+ and a consequent activation of PKC.

4. Activation of PKC by phorbol esters produces a large enhancement in action potential‐evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.
PRETREATMENT WITH THE DOPAMINE AGONIST QUINPIROLE INHIBITS CENTRAL ANTIHYPERTENSIVE MECHANISMS IN RATS*
Authors: van den Buuse M. , THtton SB
Published: June 2007

1. Intravenous or central treatment of spontaneously hypertensive rats (SHR) with the dopamine D2 receptor agonist quinpirole caused a short‐lasting pressor response with little effect on heart rate.

2. At 30 min after intravenous administration of quinpirole, the antihypertensive effect of rilmenidine was significantly inhibited. This interaction of quinpirole and rilmenidine was similarly observed when quinpirole was administered either intravenously (0.3 or 0.1 mg/kg), in the lateral cerebral ventricles (0.1 mg/kg) or intracisternally (0.1 mg/kg) or when rilmenidine was administered intravenously (1 mg/kg) or intracisternally (0.1 mg/kg).

3. The apparent desensitization to the antihypertensive effect of rilmenidine 30 min after pretreatment with quinpirole was not observed after a 4 or 24 h interval.

4. These data suggest that quinpirole has prolonged effects on central sympathetic vasomotor mechanisms that are the target of centrally acting antihypertensive drugs. These and previous results show a functional interaction between central dopamine D2 receptor activation and sympathetic responses mediated by a wide range of different receptors, including imidazoline and 5‐hydroxytryptamine 5‐HT1A‐receptors and (α‐adrenoceptors.
FAULTY INDUCTION OF BLOOD‐BRAIN BARRIER FUNCTIONS BY ASTROCYTES ISOLATED FROM STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Yamagata Kazuo , Tagami Motoki , Nara Yasuo , Fujino Hideaki , Kubota Akiyoshi , Numano Fujio , Kato§ Taiji , Yamori Yukio
Published: June 2007

1. It has been suggested that astrocytes prompt the induction of blood‐brain barrier (BBB) functions in cerebrovascular endothelial cells.

2. In the present study we have tried to elucidate the genetic differences between astrocytes isolated from Wistar‐Kyoto (WKY) control rats and astrocytes isolated from stroke‐prone spontaneously hypertensive rats (SHRSP).

3. We show that endothelial cells develop tight junction‐like structures, a reduction in vesicular transport and high electrical resistance when they are co‐cultured with astrocytes isolated from WKY rats. In contrast, SHRSP astrocytes have less of an ability to induce BBB functions than do WKY astrocytes.

4. In addition, we demonstrate that SHRSP astrocytes produce enormous quantities of lactic acid when cerebral ischaemia develops. The decrease in pH causes astrocyte swelling and damages BBB functions.

5. Consequently, we reason that genetically weak functions in astrocytes cause disruptions of BBB function and result in widespread cerebral lesions in SHRSP.
EFFECTS OF ACIDOSIS OR ALKALOSIS ON THE ACTIONS OF NIFEDIPINE ON EXCITATION‐CONTRACTION COUPLING IN THE RAT TAIL ARTERY
Authors: Achike Francis I. , Mohamad Rohaini , Dai Soter , Ogle Clive W.
Published: June 2007

1. The clinical success of calcium channel blockers in the management of organ ischaemia is less than theoretically anticipated. Blood gas/pH changes are associated with organ ischaemia; therefore, we studied the possibility that pH changes could alter the pharmacological effects of the calcium channel blocker nifedipine on rat tail artery contracted by either noradrenaline (NA) or potassium.

2. Segments (2‐2.5 cm) of the proximal third of the male Sprague‐Dawley rat tail ventral artery were initially bathed and perfused with a physiological salt solution (PSS; pH 7.48) for 25‐30 min, after which time bathing/perfusion was continued with a nominally calcium‐free PSS made acidotic (pH7.20), alkalotic (pH 7.67) or unaltered (control). After equilibration, the perfusion pressure (PP) responses to increasing concentrations of calcium in the presence of NA (3.0 μmoI/L) or potassium (100 mmol/L) with nifedipine or its vehicle were recorded.

3. The calcium sensitivity of potassium‐ or NA‐stimulated rat tail arteries was reduced during acidosis, as was the maximum PPin potassium‐ but not NA‐stimulated tissues. Alkalosis reduced the calcium sensitivity in potassium‐ but not NA‐stimulated contraction and had no effect on maximum PP.

4. The inhibitory effect of nifedipine (0.6 mUmol/L) on contraction was enhanced during acidosis in either NA‐ or potassium‐stimulated arteries and also during alkalosis in NA‐treated arteries, although it had little effect during normal conditions.

5. The results indicate that changes in pH alter the vascular contractility profile in a manner dependent on the excitation‐contraction coupling mode. The calcium antagonistic effect of nifedipine is pH dependent and it is suggested that pH changes associated with ischaemic conditions may alter the therapeutic profile of nifedipine.
INSULIN RESISTANCE SYNDROME IN AUSTRALIAN ABORIGINAL PEOPLE
Authors: Rowley Kevin G. , Best James D. , McDermott Robyn , Green Elizabeth A. , Piers L Sunil , O'Dea Kerin
Published: June 2007

1. Like many indigenous populations, Australian Aboriginal people have developed high rates of obesity, non‐insulin‐dependent diabetes mellitus (NIDDM) and cardiovascular and renal disease following the transition from a traditional to an ‘urbanized’ lifestyle. These conditions tend to cluster as part of the insulin resistance syndrome.

2. The prevalence of overweight people and obesity in Australian Aboriginal populations ranges from 0% in communities with a traditionally orientated lifestyle to well over 50% in the worst affected communities. There is a predominantly central pattern of fat deposition in both men and women, which is associated with greater insulin resistance and cardiovascular risk than is peripheral fat deposition.

3. Data from four previously published, population‐based surveys in Aboriginal communities were combined to give a cohort of 1079 subjects of 15 years and older. Several conditions of the insulin resistance syndrome had a strong, positive association with increasing body mass index (BMI): NIDDM (both cross‐sectionally and longitudinally), hypertension, dyslip‐idaemia and albuminuria. Remaining lean (BMI< 20 kg/m2) protected even older Aboriginal people from these conditions to a large extent.

4. Community based programmes to increase physical activity and improve dietary quality are likely to be the major means by which conditions associated with insulin resistance can be prevented in Aboriginal populations.
SYMPATHETIC BURST ACTIVITY: CHARACTERISTICS AND SIGNIFICANCE
Authors: McAllen Robin M. , Malpas Simon C.
Published: June 2007

1. The activity recorded from mammalian sympathetic nerves comes in bursts, which result from large numbers of fibres firing synchronously.

2. Human sympathetic nerve activity behaves similarly to that in animals, although burst rates may be lower.

3. Vasomotor, cardiac and sudomotor nerve fibres all fire in bursts. Whether other sympathetic pathways do so is unknown.

4. Sympathetic activity is intrinsically ‘bursty’ but not intrinsically regular.

5. Bursting is a population phenomenon, not usually evident in the firing of individual neurons.

6. Bursts in post‐ganglionic nerves are driven by synchronously firing preganglionic neurons.

7. The origin of bursts remains controversial. Preganglionic neuron properties are likely to be important in at least shaping bursts.

8. Burst amplitude, which reflects the number of fibres firing together, and burst probability are controlled independently.

9. Baroreceptors affect burst probability over a wide range, but have less effect on mean burst amplitude. How they affect burst timing within the cardiac cycle is discussed.

10. Burst probability is determined ‘downstream’ of the rostral ventrolateral medulla, implicating either the spinal cord or recurrent brainstem connections in burst generation.

11. Neuroeffector responses are too slow to follow individual bursts. However, bursting will promote spatial facilitation at both ganglionic and effector levels, which may increase the dynamic range of neural control.
EFFECT OF DIETARY SALT LOADING AND HIGH‐CALCIUM DIET ON VASCULAR SMOOTH MUSCLE RESPONSES AND ENDOTHELIUM FUNCTION IN RATS
Authors: Adegunloye Banji J. , Sofola Olusoga A.
Published: June 2007

1. The present study examined the effects of concurrent manipulation of dietary calcium and salt on contractile responses of vascular smooth muscle (VSM) and endothelial function of aortic rings from Sprague‐Dawley rats.

2. Salt loading enhanced the contractile response of the aortic rings to noradrenaline (NA), an effect that was blunted by a high calciu. intake.

3. Removal of the endothelium and incubation of aortic rings in physiological salt solution containing methylene blue increased the sensitivity of the rings t. NA.

4. The increase in the sensitivity of aortic rings induced by endothelium removal was more pronounced in aortic rings from salt‐loade. rats.

5. Acetylcholine caused similar degrees of relaxation in all experimental groups, but the relaxation to histamine was smalle. (P < 0.05) in salt‐loaded rats than in other groups of rats; however, after removal of the endothelium, the contractile response to histamine was higher in salt‐loaded rats.

6. The results indicate that the hypersensitivity of isolated aortic rings to agonists, as observed in salt‐loaded rats, is due to altered responses of the VSM and not as a result of changes in the endothelium. In addition, salt loading tends to increase the synthesis of endothelium‐dependent relaxing factor. The ability of salt loading to enhance the contractile responses of VSM to agonists can be prevented by supplementing the diet with high calcium.
PREVENTATIVE AND THERAPEUTIC EFFECTS OF AE0047 ON RENAL INJURY IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Hayashi Kazutaka , Koyama Mamoru , Kido Hideaki , Egi Yasuhiro , Kubo Yoshiji , Shinyama Hiroshi , Iwamoto Minori , Nakamura Norifumi , Kagitani Yoshio
Published: June 2007

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of nitrendipine in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. In the preventative study, drug administration was started before the appearance of renal injury, such as proteinuria. Treatment for 6 weeks with AE0047 (1 and 3 mg/kg, p.o.) led to a dose‐related reduction in systolic blood pressure (SBP). Nitrendipine, at doses of 10 and 30 mg/kg, also lowered SBP to a similar degree to that seen with AE0047 at 1 and 3 mg/kg, respectively.

3. In the vehicle‐administered SHRSP group, urinary excretion of protei. (UproteinV) increased progressively from 14 weeks of age for another 6 weeks. AE0047 at both doses maintained UproteinV within normal levels throughout the experimental period. However, the elevation of UproteinV was only inhibited in the 30 mg/kg nitrendipine‐treated group. Urinary N‐acetyl‐β‐D‐glucosaminide (NAG) activity in the vehicle‐treated SHRSP group was elevated. Urinary NAG activity remained at a low level only in AE0047‐treated groups.

4. Histopathological examination revealed severe lesion. (i.e. fibrinoid necrosis, proliferative vasculitis and glomerular lesions) of the kidney in SHRSP. AE0047 treatment at each dose attenuated the development of renal lesions in SHRSP. In contrast, nitrendipine, at 10 mg/kg, was ineffective against the development of renal lesions. Although nitrendipine at 30 mg/kg suppressed the development of renal lesions, this effect was still weaker than that seen with AE0047 at 1 mg/kg.

5. In the therapeutic study, drugs were administered to 17‐week‐old SHRSP with moderate renal damage for 10 days. Treatment with AE0047 (1 and 3 mg/kg) produced dose‐dependent decreases in UproteinV. In the nitrendipine‐treated group, UproteinV tended to decrease but the changes were not significant.

6. Histopathological studies revealed that 3 mg/kg AE0047 improved renal lesions, such as fibrinoid necrosis, proliferative vasculitis and glomerular lesions, whereas 30 mg/kg nitrendipine di. not.

7. Taken together, the results indicate that AE0047 is capable of preventing proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore, AE0047 improves proteinuria and renal lesions in proteinuria‐established SHRSP. Thus, AE0047 may have therapeutic potential in suppressing either the development or the progression of renal disease in hypertensive patients.