bluuebunny/crossref_metadata_2025 huggingface dataset:
RECENT INSIGHTS INTO DIETARY FATS AND CARDIOVASCULAR DISEASE
Authors: Dimmitt Simon B.
Published: June 2007

1. Fat deposition in the arterial intima is fundamental to the atheroma process. Circulating lipoproteins are thought to be the source of much of the deposited fat. The interplay of dietary fat has not been fully clarified.

2. Observational studies have furnished evidence of relationships between the different dietary fats and clinical cardiovascular events. In these, total fat and in particular, saturated fat appear culprit. Mono‐unsaturated (MUFA) and polyunsaturated (PUFA) fats have less consistent relationships with cardiovascular disease, though all classes of fatty acid are found in atheroma.

3. Comparing the effects on lipoproteins of saturates, mono‐unsaturates and polyunsaturates, they all increase high density lipoproteins (HDL) and reduce triglycerides when substituted isocalorically for carbohydrate. Saturates increase low density lipoproteins (LDL), while PUFA > MIJFA reduce LDL.

4. Upon oxidative modification, lipoproteins are more liable to arterial deposition and, in vitro at least, LDL oxidizability is enhanced by enrichment with PUFA.

5. Trans‐MUFA have some unique properties in that they somewhat resemble saturates and seem to predispose to coronary disease, quite possibly because of their adverse effects on LDL, HDL and Lp(a) levels.

6. ω‐3 fatty acids seem unique among the dietary fats in that they inhibit thrombosis and platelet aggregation, and can lower blood pressure.

7. The net effect of these various potential influences of fatty acids on atherogenesis in vivo is unclear. It may well be that all fats, with the exception of the ω‐3 class, are detrimental with respect to atherogenesis. Modification of the diet, with particular attention to fat, has been demonstrated to reduce clinical coronary events in several studies. Restriction of all fats, save for that in fish, preferably along with weight reduction, appears desirable in order to effectively reduce cardiovascular disease risk.
MECHANISMS FOR REDUCTION OF CARDIOVASCULAR RISK BY REGULAR EXERCISE
Authors: Jennings Garry L. R.
Published: June 2007

1. Regular aerobic exercise causes cardiovascular, neural, humoral and metabolic changes. Many of these are likely to influence cardiovascular risk and the changes vary according to the level and duration of increased physical activity.

2. The case for exercise exerting beneficial effects derives from epidemiological data showing that sedentary subjects have, on average, double the risk of cardiovascular disease of active individuals. Post‐infarct rehabilitation studies are also consistent with a beneficial effect of exercise. Large randomized controlled intervention studies have not been performed.

3. These benefits may be due to the effects of regular exercise on risk factors, direct effects on atheromatous vessels, or improvement in survivability in established coronary heart disease by reducing arrythmias or increasing tolerance of ischaemia.

4. There are direct effects of regular exercise on blood pressure (BP) and lipid profiles. These occur at different levels of physical activity. Other changes which would be expected to reduce cardiovascular risk include increased insulin sensitivity, reduced sympathetic activity and increased gain of the baro‐receptor‐heart rate reflex and increased arterial compliance.

5. In hypertensives these changes may improve outcomes, irrespective of the reduction in BP reported in some randomized controlled intervention studies.
ASSESSMENT OF NUTRITION AND PHYSICAL ACTIVITY EDUCATION PROGRAMMES IN CHILDREN
Authors: Burke V. , Beilin L. J. , Milligan R. , Thompson C.
Published: June 2007

1. Studies in children relating blood lipids to the extent of atherosclerosis at post‐mortem suggest a link between risk factors for cardiovascular disease in childhood and adult life. Tracking of blood pressure (BP) and cholesterol from childhood also supports this association. However, prospective studies have not yet established the outcome in children with increased levels of risk factors.

2. In a controlled trial in Perth, Western Australia, involving over 1000 10–12 year old children, fitness was improved by physical activity programmes which were associated with a greater fall in diastolic BP and triceps skinfolds in girls compared with controls. Sugar intake decreased in boys and fat intake fell in girls, mainly affecting participants in home nutrition programmes.

3. In higher risk children, identified by cluster analysis, major benefits were associated with the fitness and home nutrition programmes. Physical activity combined with involvement of the family in nutrition education is likely to be the most successful approach to modifying lifestyle in children, including those with higher levels of risk.

4. Undernutrition by too rigid restriction of fat intake must be avoided in young children who need calorie‐dense foods. Undernutrition, in itself, may predispose to cardiovascular disease in later life. Programmes should aim to establish a prudent diet appropriate to the age of the child combined with physical activity. As regular activity and a healthy diet in adult life will reduce risks of cardiovascular disease it is likely that childhood education will establish lifestyle habits of potential long‐term benefit.
ECONOMIC COMPARISON OF DRUG AND LIFESTYLE TREATMENT OF CARDIOVASCULAR RISK FACTORS IN HIGH‐RISK PATIENTS
Authors: Millar J. A.
Published: June 2007

1. Lifestyle interventions are routinely used in the treatment of cardiovascular risk factors in individual patients but their cost‐effectiveness relative to drug treatment is largely unknown.

2. Drug treatment is effective at normalizing risk factors and is known to decrease morbidity and mortality though costs may be high. Lifestyle interventions carry a significant potential to reduce expenditure on drugs, but prospective studies on cost‐effectiveness of lifestyle interventions favour drug treatment.

3. According to current evidence, lifestyle intervention in high‐risk patients is not more cost‐effective than drug treatment.
EFFECTS OF DIABETES ON CALCIUM UPTAKE BY RAT BRUSH BORDER MEMBRANE VESICLES
Authors: Schedl Harold P. , Christensen Karla K. , Ronnenberg William C.
Published: June 2007

1. We investigated the mechanism of decreased transmucosal calcium transport in the gut of the diabetic rat by comparing calcium uptake by brush border membrane vesicles from control and streptozotocin diabetic rats at 5 days. Brush border calcium uptake consists of saturable and non‐saturable components. Saturable uptake is mediated by a specific mobile carrier mechanism and is defined by Vmax (saturable uptake of calcium at infinite medium calcium concentration) and KT (calcium concentration at Vmax/2). Non‐saturable uptake is defined by kD (rate constant for non‐saturable uptake per unit calcium concentration), and comprises both diffusive and surface binding components of calcium uptake.

2. We found both saturable and non‐saturable calcium uptake to be decreased (P < 0.05) in diabetes. Comparing control and diabetic, Vmax was 247 compared to 152 (data are pmol/mg protein per 3 s); kD was 285 compared to 172 (data are pmol/mg protein per 3 s at 1 mmol/L calcium); and KT (mmol/L) did not differ between groups, 0.070 compared to 0.057.

3. The decreased Vmax in the setting of unchanged Kt in vesicles from diabetics is consistent with decreased calcium transporter specific activity, rather than with altered transporter function.

4. Since (i) Vmax is decreased by vitamin D deficiency in the normal rat, and (ii) circulating 1α,25‐dihydroxycholecalciferol is decreased in the diabetic rat, decreased Vmax in the diabetic may be related to the low 1α,25‐dihydroxycholecalciferol.

5. Since vitamin D deficiency does not alter kD in the normal rat, the decreased kD in diabetes may be an effect of diabetes on the membrane. In conclusion, decreased transmucosal calcium transport in diabetes is, at least in part, the consequence of decreased brush border uptake.
REGULATION OF NUCLEAR TRANSCRIPTION FACTORS BY STRESS SIGNALS
Authors: Woodgett James R. , Avruch Joseph , Kyriakis John M.
Published: June 2007

1. A diverse array of stressful stimuli induces changes in gene expression via post‐translational modification of transcription factors.

2. Study of activator protein (AP‐1) transcription factor regulation has revealed a novel family of protein‐serine kinases. Molecular cloning and expression of these proteins have demonstrated their specific activation by stress stimuli such as UV irradiation, heat, ischaemia/reperfusion and metabolic toxins.

3. Dissection of the regulation of the stress‐activated protein kinases has revealed a similar but distinct mechanism to mitogen‐activated protein kinases suggesting that cellular responses to stress may partially overlap with normal growth responses and have common nuclear targets.
PRACTICAL APPLICATIONS OF NEURONAL TISSUE CULTURE IN IN VITRO TOXICOLOGY
Authors: Sawyer Thomas W.
Published: June 2007

1. Primary chick embryo forebrain neurones are relatively easy to culture and are quite resilient to treatment manipulation. These characteristics have allowed application in a surprisingly diverse number of areas.

2. These cultures have been used to investigate the anti‐cholinesterase potencies of many organophosphate (OP) nerve agents and insecticides.

3. These cultures have been used to quantitate levels of OP in ‘spiked’ unknowns and in OP‐contaminated soil samples.

4. These cells have also been used to test a variety of compounds using the MTT and neutral red cytotoxicity assays.
Ca2+‐DEPENDENT AND ‐INDEPENDENT MECHANISMS OF ISCHAEMIA‐EVOKED RELEASE OF [3H]‐DOPAMINE FROM RAT STRIATAL SLICES
Authors: Kim K. W. , Kim D. C. , Kim Y. H. , Eun Y. A. , Kim H. I. , Cho K. P.
Published: June 2007

1. Ischaemia was induced by 5 min of deprivation of glucose and an additional 5 min of deprivation of glucose and oxygen from Mg2+‐free artificial cerebrospinal fluid in vitro.

2. During the ischaemic period, 11 ± 1.5% of the total [3H]‐dopamine ([3H]‐D A) was released into the incubation medium.

3. Ischaemia‐evoked release of [3H]‐DA from striatal slices was attenuated by tetrodotoxin (TTX), MgSO4, dizocilpine, ketamine, 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX), or carbetapentane.

4. Release of [3H]‐DA was attenuated by verapamil, ω‐conotoxin GVIA and dantrolene.

5. Nomifensin inhibited the ischaemia‐induced release of [3H]‐DA.

6. Omission of Ca2+ from incubation media potentiated ischaemia‐evoked [3H]‐DA release. The inhibitory effect of nomifensin was potentiated in Ca2+‐free incubation media.

7. These results suggest that ischaemia induces release of [3H]‐DA by dual mechanisms; one is Ca2+‐dependent exocytosis and the other is reversal of transporter.
GLUTAMATE‐INDUCED CALCIUM LOADS: EFFECTS ON ENERGY METABOLISM AND NEURONAL VIABILITY
Authors: Thayer Stanley A. , Wang Guang Jian
Published: June 2007

1. Glutamate‐induced increases in intracellular free Ca2+ concentration ([Ca2+]i) were recorded from cultured rat hippocampal neurons with single cell microfluorometry. The [Ca2+]i increase did not correlate with glutamate‐induced cell death, consistent with the idea that Ca2+ accumulates in an intracellular store, and that loading this store might be toxic.

2. Glutamate‐induced Ca2+ loads were buffered by a low‐affinity, high‐capacity process that was inhibited by the mitochondrial uncoupling agent FCCP and modulated by intracellular Na+.

3. Glutamate‐induced Ca2+ loads also produced an intracellular acidification. The acidification was prevented by the metabolic inhibitor 2‐deoxyglucose, mimicked by Ba2+, and inhibited by microinjection of ruthenium red.

4. These data are consistent with the hypothesis that mitochondria sequester glutamate‐induced Ca2+ loads producing a metabolic acidosis; metabolic stress may contribute to glutamate‐induced neuronal death.
CROMAKALIM SUPPRESSES HYPERTONIC SALINE‐INDUCED RENAL VASOCONSTRICTION IN ANAESTHETIZED DOGS
Authors: Ogasawara Aichi , Hirano Takahiro , Hisa Hiroaki , Satoh Susumu
Published: June 2007

1. Intrarenal arterial infusion of hypertonic saline (HS) transiently increased and then gradually reduced renal blood flow (RBF) in anaesthetized dogs. Glomerular filtration rate (GFR) but not filtration fraction decreased at the end of the infusion.

2. In the presence of a potassium channel opener cromakalim (0.3 μg/kg per min), HS infusion failed to reduce RBF; the initial increase in RBF was maintained throughout the infusion. Since cromakalim also prevented the decrease in GFR, HS infusion lowered filtration fraction.

3. The results suggest that cromakalim inhibits both pre‐and postglomerular vasoconstriction induced by HS infusion.
ENDOTHELIN‐1 AND THE REGULATION OF VASCULAR TONE
Authors: La Mylinh , Reid Julianne J.
Published: June 2007

1. In 1988, Yanagisawa et al. reported the presence of a potent peptide from the supernatant of porcine endothelial cells. This was later named endothelin‐1 (ET‐1) and was found to belong to a new family of vasoconstrictor peptides. There are at least three isoforms of endothelin: ET‐1, endothelin‐2 and endothelin‐3.

2. ET‐1 is produced from a larger precursor molecule by endothelin converting enzyme (ECE); there may be a number of ECE but the most physiologically relevant appears to be a membrane‐bound neutral metalloprotease. The endothelin precursor is produced on demand and is regulated at the mRNA level.

3. Two subtypes of mammalian endothelin receptors have been cloned and sequenced: ETa receptors which mediate vasoconstriction and ETe receptors which mediate both vasoconstriction and vasodilatation. However, functional studies have indicated that other subtypes of endothelin receptors may exist.

4. ET‐1 has a wide range of biological actions apart from its direct effects on vascular tone, including constriction of non‐vascular smooth muscle, cardiac effects, mitogenesis and stimulation of the release of hormones such as atrial natriuretic peptide and prostacyclin. At low concentrations which have no direct vasoconstrictor action, ET‐1 potentiates the effect of other vasoconstrictor agonists.

5. The precise role of ET‐1 in health and disease is not well defined at present; however, there are indications that it may have a role in the pathogenesis of some cardiovascular disease states, including subarachnoid haemorrhage, renal ischaemia and certain types of hypertension.
ELECTROPHYSIOLOGICAL EFFECTS OF CHANGROLIN, AN ANTIARRHYTHMIC AGENT DERIVED FROMDICHROA FEBRIFUGA, ON GUINEA‐PIG AND RABBIT HEART CELLS
Authors: Lu Ling‐Ling , Habuchi Yoshizumi , Tanaka Hideo , Morikawat Junichiro
Published: June 2007

1. The electrophysiological effects of changrolin (CRL), a Chinese antiarrhythmic drug derived from a traditional anti‐malarial plant, were examined using the whole‐cell patch‐clamp method on single cells isolated from guinea‐pig and rabbit hearts.

2. At a clinically relevant concentration of 50μmol/L changrolin inhibited Ica. by 19.3 ± 6.0% and 17.3 ± 2.6% in guinea‐pig and rabbit ventricular cells, respectively. The voltage‐dependent channel availability curve was not affected. The CRL effect was enhanced to a small extent during a repetitive stimulation at 2 Hz.

3. Inawas resistant to CRL and the channel availability curve was also unaffected. A small use‐dependent inhibition was observed only when the Inawas elicited at 5 Hz in the presence of 300 μmol/L CRL.

4. At 50 μmol/L, CRL did not affect the time‐independent inward rectifier and the delayed rectifier K+currents (Iki and Ik, respectively), but inhibited the transient outward current (Ito) by 17.7 ± 2.4%. Changrolin significantly shortened the action potential duration in both guinea‐pig and rabbit ventricular cells.

5. In conclusion, CRL inhibits Icaand Ito but has little effect on Ina.
COMPARISON OF NEURITE OUTGROWTH WITH NEUROFILAMENT PROTEIN SUBUNIT LEVELS IN NEUROBLASTOMA CELLS FOLLOWING MERCURIC OXIDE EXPOSURE
Authors: Abdulla Elizabeth McFarlane , Calaminici Mariarita , Campbell Iain C.
Published: June 2007

1. The objectives of the study were to establish that inhibition of neuronal differentiation in culture (assessed by neurite outgrowth) can be used as a broad spectrum in vitro measure of neurotoxicity.

2. To establish whether a rapid measure of neurite outgrowth could be used. Thus the study examined the relationship between the degree of neurite outgrowth assessed directly by image analysis and neurofilament protein subunit levels measured by an ELISA.

3. SKNSH neuroblastoma cells, exposed for up to 6 days to mercuric chloride during initiation and continuation of differentiation, had lower levels of neurofilament proteins than unexposed cells.

4. Preliminary data from parallel examinations of neurite outgrowth assessed by image analysis and neurofilament protein subunit levels assessed by ELISA support a correlation when neurofilament protein levels are decreased by sub‐cytotoxic doses of mercuric chloride in SKNSH cells.
ALTERATION OF THE MORPHOLOGY AND NEUROCHEMISTRY OF THE DEVELOPING MAMMALIAN NERVOUS SYSTEM BY HYDROGEN SULPHIDE
Authors: Roth S. H. , Skrajny B. , Reiffenstein R. J.
Published: June 2007

1. Hydrogen sulphide (H2S) is a broad spectrum toxicant that occurs widely in nature and is also released by a variety of industrial activities and processes.

2. The central nervous system (CNS) appears to be the major target organ.

3. There is great potential for insult or injury to the developing or immature CNS.

4. The risks of chronic or repeated exposures to low concentrations have not been well defined.

5. Exposure to low concentrations of H2S to time‐pregnant rats from day 5 postcoitus until day 21 postnatal results in architectural modification of cerebellar Purkinje cells, alteration of putative amino acid neurotransmitters and changes in monoamine levels in the developing rat brain up to day 21 postnatal.

6. H2S‐induced alterations in monoamine tissue levels observed in the developing rat brain return to control values if exposure is discontinued during development, that is, at day 21 postnatal.
GENE EXPRESSION OF ENDOTHELIN RECEPTORS IN AORTIC CELLS FROM CYCLOSPORINE‐INDUCED HYPERTENSIVE RATS
Authors: Iwai Junko , Kanayama Yoshiharu , Negoro Nobuo , Okamura Mikio , Takeda Tadanao
Published: June 2007

1. We examined preproendothelin‐1, ETA and ETb receptor mRNA levels in aortic endothelial and smooth muscle cells from cyclosporine (CyA)‐induced hypertensive rats using the reverse transcription polymerase chain reaction method.

2. Aortic endothelial preproendothelin‐1 mRNA expression was about 1.5‐fold higher, while that of ETB receptor mRNA was markedly decreased in CyA‐treated rats compared with those in controls.

3. The expression of ETA receptor mRNA in smooth muscle cells from CyA‐induced hypertensive rats was increased about two‐fold over that in cells from control animals.

4. Thus, increased endothelial preproendothelin‐1, and ETa receptor mRNA levels in smooth muscle cells, which are concomitant with the decrease in ETB receptor mRNA levels in endothelium, may contribute to CyA‐induced hypertension in rats.
POSITIVE INOTROPIC RESPONSES OF THE SODIUM CHANNEL MODULATOR BDF 9148 IN DISEASED RAT MYOCARDIUM
Authors: Hoey Andrew , Nankervis Richard , Brown Lindsay
Published: June 2007

1. This study has defined the positive inotropic responses to the sodium channel modulator BDF 9148 in rats with hypertension, thyroid dysfunction, diabetes or dwarfism. Concentration‐response curves to BDF 9148 and calcium chloride were determined in isolated left atria and left ventricular papillary muscles.

2. BDF 9148 increased force of contraction in left ventricular papillary muscles in all disease states with maximal responses comparable to calcium chloride. BDF 9148 potency was significantly decreased in muscles from diabetic rats only.

3. BDF 9148 produced similar responses in left atria except from hyperthyroid rats where negative inotropic responses only were measured. This exception confirms that the left atria is an imperfect model for ventricular responsiveness.

4. Thus, the increase in force of contraction in the ventricles as a consequence of sodium channel modulation by BDF 9148 is maintained in these disease states unlike responses to α‐or β‐adrenoceptor agonists.
RENAL MEDULLA AND BRADYKININ DURING THE DEVELOPMENT OF HYPERTENSION IN SHR
Authors: O'Sullivan Joseph B. , Bertram John F. , Harrap Stephen B.
Published: June 2007

1. The long‐term reduction in blood pressure following ACE inhibitor treatment in young spontaneously hypertensive rats (SHR) appears to depend on both the kidney and brady‐kinin.

2. The aim of this experiment was to examine the effects of ACE inhibition and bradykinin on renal morphology and blood pressure in SHR.

3. Between 6 and 10 weeks of age male SHR received one of four treatments: water (n = 26), ramipril (1 mg/kg per day; n = 24), ramipril (1 mg/kg per day) plus Hoe 140 (0.5 mg/kg per day; n = 25) or Hoe 140 (0.5 mg/kg per day; n= 25).

4. Renal medullary and cortical volumes were determined stereologically at 10 and 20 weeks of age.

5. After 4 weeks of treatment, ramipril reduced the size of the renal medulla while Hoe 140 increased medullary volumes compared to control. Ten weeks after treatment was stopped the renal medulla of the ramipril group had returned to normal, however, there was a persistent increase in medullary volume of both Hoe 140 treated groups.

6. Our results imply that bradykinin may influence the size of the renal medulla which may have important effects on the development of hypertension in SHR.
THE EFFECT OF INDUCED REFLECTIONS ON HUMAN ARTERIAL WAVEFORMS
Authors: Kobler H. , Henderson R. , Lal S. , Hart M. , Hunyor S.
Published: June 2007

1. External compression of the human brachial artery results in waveform reflection.

2. Resonant waves are found superimposed on the original blood pressure signal.

3. The mechanism may be likened to the operation of an organ pipe with reflections at both ends of an arterial segment.

4. This has implications for measurements in arteries where external pressure is applied.
RENIN mRNA CONCENTRATION IN RAT HYPOTHALAMUS IS DECREASED BY ENALAPRIL
Authors: Lou Yi‐kun , Liu Dennis T. , Whitworth Judith A. , Morris Brian J.
Published: June 2007

1. Renin mRNA is expressed in several extrarenal tissues, including brain. The aim of the present study was to quantify renin mRNA in the hypothalamus in response to a low NaCl diet and angiotensin converting enzyme inhibitor treatment, both of which are well‐known stimuli of renin mRNA in kidney.

2. Groups of six Sprague‐Dawley rats were given either a normal diet, low NaCl chow (0.04% NaCl), enalapril (0.25 mg/mL in drinking water), or low NaCl + enalapril, for 7 days. Renin mRNA in the hypothalamus was quantified by a competitive reverse transcriptase‐polymerase chain reaction (RTPCR) technique.

3. Renin mRNA concentration in the hypothalamus of rats receiving a normal diet was 52 ± 3 S.E. fg/μg total RNA. Low NaCl had no effect (57 ± 7), whereas values were significantly lower in rats treated with enalapril, either given alone (38 ± 2; P= 0.002) or combined with a low NaCl diet (33± 4; P= 0.003).

4. In conclusion, we have quantified renin mRNA in the rat hypothalamus and shown that it can be suppressed significantly by enalapril. This response is opposite to that seen in the kidney after enalapril.
WIRING UP THE VISUAL SYSTEM
Authors: Beazley L. D. , Dunlop S. A. , Chelvanyagam D. K. , Ross W. M.
Published: June 2007

1. In this review we describe some of our recent studies on the developing marsupial visual pathway. The description focuses on retinal ganglion cells, considering the formation of their dendritic trees, the outgrowth of axons and the formation of connections within the brain.

2. Both dendritic trees and outgrowing axons undergo a period of exuberance, followed by one of refinement. The dendritic tree transiently develops a more complex branching pattern than is found in adults. Short side branches, referred to as spines, are a feature of immature dendrites and, to a lesser extent, of axons. These structures are mostly lost as development proceeds. However, they are retained on the dendritic trees of small‐field ganglion cells and, for a proportion of axons, on that part within the nerve fibre layer of the retina. Although most axons navigate fairly direct routes towards their targets, a minority follow inappropriate courses, such as doubling back towards the eye or entering the opposite optic nerve at the chiasm. As such errant axons are not seen in the adult, we assume that their parent cell bodies die during development.

3. Throughout development, optic axons are arranged in an approximate retinotopic order along the length of the visual pathway; as a result, axons approach the visual centres aligned to form, at least, a crude retinotopic map. Axons from dorsal and ventral retina exchange locations along the optic nerve and in this way correct for the inversion of the image brought about by the lens.

4. We also describe the topography of cells in the retinal ganglion cell layer and the organization of the optic nerve in an unusual marsupial, the honey possum (Tarsips rostratus). Unexpected features in the adult were the low proportion of displaced amacrine to ganglion cells and an unmyelinated macular outflow in the retro‐bulbar portion of the optic nerve.
MODULATION OF VASOCONSTRICTION BY ENDOTHELIUM‐DERIVED NITRIC OXIDE: THE INFLUENCE OF VASCULAR DISEASE
Authors: Woodman Owen L.
Published: June 2007

1. The endothelium makes a significant contribution to the regulation of vascular tone through the release of potent vasodilator agents such as nitric oxide (NO) and prostacyclin (PGI2) as well as vasoconstrictor compounds such as endothelin. Recognition of this function of the endothelium has created a new focus for the investigation of vasoconstrictor activity under physiological and pathological conditions.

2. It has been well established that removal of the endothelium enhances responses to a variety of contractile agents in conductance arteries and that such modulation is predominantly due to the release of NO. The use of selective inhibitors of NO synthesis has confirmed that the endothelium‐derived nitric oxide also modulates constriction in resistance vessels.

3. In a number of cardiovascular disease states there is impairment of endothelial function. Thus one of the consequences of atherosclerosis, hypertension and ischaemia is a reduction in endothelium‐dependent vasodilatation, both at a basal level and in response to endogenous and exogenous stimuli. In addition, enhanced responses to vasoconstrictors have been reported in those disease states. Such observations have led to the attractive hypothesis that enhanced constriction in vascular disease results from attenuate NO‐induced dilatation. However, whilst there is some evidence that pathological impairment of endothelial function is accompanied by increased constrictor activity, particularly where serotonergic mechanisms are involved, it is inappropriate to make the general assumption that where disease impairs NO activity there will also be increased sensitivity to all constrictor stimuli.
HAEMODYNAMIC RESPONSES TO RAT ADRENOMEDULLIN IN ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ishiyama Yuichiro , Kitamura Kazuo , Ichiki Yoshinari , Sakata Junichiro , Kida Osamu , † Kenji Kangawa , Eto Tanenao
Published: June 2007

1. The haemodynamic effects of rat adrenomedullin (AM), a novel hypotensive peptide, were examined in anaesthetized 16–18 week old spontaneously hypertensive rats (SHR) and Wistar‐Kyoto rats (WKY).

2. An intravenous injection of rat AM dose‐dependently reduced the mean blood pressure (MBP) with a concomitant fall in total peripheral resistance index (TPRI) and an increase in cardiac index (CI) in both strains of rats. Per cent changes in MBP, TPRI and CI were not different between SHR and WKY.

3. The plasma half‐life of rat AM in SHR was similar to that in WKY when it was administered at the dose of 1.0 nmol/kg.

4. These findings indicate that AM has a potent vasorelaxant activity in both SHR and WKY. The haemodynamic responsiveness to exogenous AM and its pharmaeokinetics in SHR were comparable with those in WKY.
CILIARY ULTRASTRUCTURE AND BEATING ACTIVITY IN RAT AND GUINEA‐PIG RESPIRATORY MUCOSA
Authors: Joki Susanna , Toskala Elina , Saano Veijo , † Juhani Nuutinen
Published: June 2007

1. The rat and the guinea‐pig are commonly used animals when the effects of drugs on ciliary activity in respiratory airways are studied. There are few data concerning the possible differences in ciliary function between these two animals.

2. Using a photodetector method we measured the ciliary beating frequency (CBF) from the upper part of the trachea, the lower part of the trachea and the distal part of the main bronchi (subsegmental bronchi) of rat and guinea‐pig respiratory tract. In addition, the structure of the cilia was studied using scanning electron microscopy (SEM).

3. CBF in the rat respiratory tract was significantly lower than in the guinea‐pigs. In the upper trachea, the CBF for rat was 12.7 beats/s and 15.3 beats/s for guinea‐pig. The respective values were 9.2/16.0 beats/s in the lower part of the trachea and 6.9/13.8 beats/s in subsegmental bronchi. In both rats and guinea‐pigs CBF was lower in the subsegmental bronchi than in the trachea (rat: 25.0–45.7%, guinea‐pig: 9.8–13.8%).

4. In addition to higher CBF, the quality of the photo‐electrical signal was better from guinea‐pig tissues, probably as a result of the larger amounts of ciliated cells and longer cilia of guinea‐pig respiratory epithelia compared to those in rat mucosa.

5. SEM showed that the rat cilia were on average shorter (3.6 vs 4.3 μm) and thinner (0.19 vs 0.22 μm) than those of the guinea‐pig. Rat mucosa was markedly less ciliated than the respiratory mucosa of the guinea‐pig.

6. Choice of animal species may affect the reliability and sensitivity of results when drug effects on ciliary function are studied. Guinea‐pig may be the most suitable choice as a laboratory animal, although guinea‐pig mucosa requires more careful handling than rat tissue in order to avoid mechanical artefacts.
WHOLE BODY AND RENAL NORADRENALINE RELEASE DURING ACUTE INFUSION OF ENDOTHELIN‐1 IN CONSCIOUS SHEEP
Authors: Mathai Michael L. , Whitworth Judith A. , McDougall John G.
Published: June 2007

1. The present study investigated in conscious sheep the response of the sympathetic nervous system to a systemic infusion of 20 nmol/h endothelin‐1 (ET‐l), using a tritiated‐noradrenaline (NA) tracer dilution technique.

2. Mean arterial pressure increased from 79 ±3 mmHg to a maximal level of 102± 12 mmHg by 30 min of ET‐1 infusion.

3. Total and renal NA kinetics were measured during this time. Total NA spillover was not affected by infusion of ET‐1. In contrast, renal NA spillover decreased from a control level of 81 ± 5 to 30 ± 14ng/min (P<0.01) after 20 min and to 27 ± 7ng/min (P<0.01) after 30 min of ET‐1 infusion.

4. The present findings are consistent with the proposal that a direct vasoconstrictor action of ET‐1 results in a paroreflex mediated reduction in renal sympathetic vasoconstrictor activity.
THE PROPORTIONAL CUMULATIVE AREA UNDER THE CURVE OF PARACETAMOL USED AS AN INDEX OF GASTRIC EMPTYING IN DIABETIC PATIENTS WITH SYMPTOMS OF GASTROPARESIS
Authors: van Wyk M. , Sommers De K. , Snyman J. R. , Moncrieff J.
Published: June 2007

1. The foreshortened 2 h method of measuring liquid gastric emptying (i.e. the proportional cumulative area under the curve of paracetamol) was utilized in diabetic patients in order to detect both gastroparesis and the influence of metoclo‐pramide, a known prokinetic drug, on this condition.

2. Metoclopramide, 10 mg intravenously, caused a significant increase in the median PCAUC from 20 min onwards.

3. In this study delayed gastric emptying was defined as a %PCAUC without pretreatment lower than the 5% percentile at 40, 60 and 90 min for normal volunteers. According to this criterion seven of the 10 patients with clinical symptoms of gastroparesis and/or peripheral neuropathy had delayed gastric emptying.

4. The PCAUC method would therefore seem to be a reliable model for investigating gastric emptying in diabetics and the effects of various prokinetic drugs on this condition.
INCREASED BLOOD PRESSURE AND CHANGES IN MEMBRANE LIPIDS ASSOCIATED WITH CHRONIC ETHANOL TREATMENT OF RATS
Authors: Puddey I. B. , Burke V. , Croft K. , Beilin L. J.
Published: June 2007

1. Changes in membrane fluidity have been proposed to contribute to the pathogenesis of ethanol‐induced hypertension possibly through changes in membrane lipid patterns, but reports are inconsistent.

2. In a controlled trial we documented ethanol‐induced changes in blood pressure and composition of membrane lipids in ethanol‐fed rats.

3. Systolic blood pressure increased significantly in the ethanol‐treated rats (9.3 mmHg, s.e.m. 2.9) compared with the control group (—1.3 mmHg, s.e.m. 2.6). Mean cholesterol content in red cell membranes did not differ significantly between ethanol‐fed and control rats. Phospholipids of aorta, red cells and kidney showed a significant decrease in the polyunsaturated to saturated fatty acid ratio, while membrane phospholipids from the heart showed a significant increase in the polyunsaturated to saturated fatty acid ratio with ethanol treatment.

4. In univariate regression blood pressure was significantly negatively related to levels of arachidonic acid in the kidney (P= 0.0013) and to linoleic acid in the aorta (P= 0.0341) and red cells (P= 0.0289). Blood pressure was not significantly related to fatty acids in the heart nor to membrane cholesterol or phospholipids.

5. Differences in fatty acid composition of phospholipids between controls and ethanol‐fed rats are consistent with altered membrane fluidity. Altered membrane function is a potential mechanism involved in ethanol‐induced hypertension.
EFFECT OF AN ANTIHYPERTENSIVE DRUG ON BRAIN ANGIOTENSIN II LEVELS IN RENAL AND SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Morishita Ryuichi , Higaki Jitsuo , Nakamura Yoshio , Aoki Motokuni , Yamada Kazuo , Moriguchi Atsushi , Rakugi Hiromi , Tomita Naruya , Tomita Sawako , Yu Hisahiro , Nakamura Fumiaki , Mikami Hiroshi , Ogihara Toshio
Published: June 2007

1. Although numerous studies suggest that brain angiotensin (AII) may play an important role in the regulation of blood pressure, it is still unclear what factors may influence brain All. In this study, we hypothesized that brain AII is influenced by circulating factors. To investigate the role of blood pressure and plasma All in brain AII level, we studied the effect of an antihypertensive drug on brain AII in two‐kidney, one‐clip (2K1C) and spontaneously hypertensive (SHR) rats.

2. Hydralazine (20mg/kg per day) and vehicle (water) were given to 2K1C rats between 2 and 6 weeks after operation and SHR for 4 weeks. In addition, vehicle was applied to sham operated rats and Wistar‐Kyoto (WKY) rats. Brain and plasma AII was measured by a highly sensitive radioimmunoassay coupled with high performance liquid chromatography.

3. Hydralazine treatment effectively lowered blood pressure to the same levei of sham‐operated and WKY rats. 2K1C rats showed significantly higher plasma All than sham rats, but hydralazine treatment did not show any change in plasma AII. Brain AII in the hypothalamus region of 2K1C rats showed a significantly higher level than sham rats. Interestingly, hydralazine treatment diminished this increase in brain AII. In contrast, SHR showed higher brain A11 levels in the hypothalamus, brainstem and cerebellum than in WKY rats, whereas there was no significant change in plasma AII concentration between SHR and WKY rats. In contrast to the results found in 2K1C rat experiments, hydralazine treatment failed to decrease brain AII levels despite lowered blood pressure.

4. In conclusion, brain AII is affected by systemic blood pressure in 2K1C hypertensive rats, but not in SHR, and the mechanisms which cause the difference between 2K1C rats and SHR are unknown in this study.
COMPARISON OF THE ATTENUATING EFFECTS OF FOUR β‐ADRENOCEPTOR AGONISTS ON RAT ISOLATED UTERUS AND AORTA
Authors: Doggrell Sheila A.
Published: June 2007

1. The ability of four 8‐adrenoceptor agonists to attenuate oxytocin (0.2,2 and 20 nmol/L) or KCI (20,40 and 80 mmol/L)‐induced Contractions of the uterus (n= 5–8 for each agonist) and the KCI (18 mmol/L)‐induced contractions of the aorta (n = 9 for each agonist) from rats, pretreated with oestradiol has been compared.

2. Isoprenaline, salbutamol, terbutaline and procaterol (0.1–10μmol/L) attenuated the contractions of the uterus and the aorta. All four agonists had similar attenuating potencies on the uterus.

3. Procaterol caused the same maximal attenuation (33%) on the aorta as the other β‐adrenoceptor agonists and is thus acting as a full β2‐adrenoceptor agonist under these experimental conditions. Isoprenaline and procaterol were much more potent than salbutamol and terbutaline in attenuating the aorta responses.

4. This study showed that isoprenaline and procaterol were potent attenuants on both the uterus and aorta whereas salbutamol and terbutaline were potent uterine but only modest aorta attenuants. This preliminary study indicates that the responsiveness of uterine and vascular tissue to certain β2‐adrenoceptors differs.
MOLECULAR AND FUNCTIONAL DIVERSITY OF K+ CHANNELS
Authors: Christie MacDonald J.
Published: June 2007

1. Amino acid sequences encoding K+ channels belong to several subfamilies of the voltage‐gated ion channel superfamily which includes Na2+‐, Ca2+‐, and cyclic nucleotide gated channels. The Kv family is the largest group, and encodes delayed rectifier, A‐type, and large conductance Ca2+ activated K+ channels.

2. The α‐subunits of Kv channels form as tetramers of four independent subunits. Each subunit has six membrane spanning regions and a pore forming ‘P’ region. Subunits belong to subfamilies (Kv1–4, BK, Eag) comprising multiple members, each of which has distinct properties resembling each of the major types of native Kv channel when expressed as homomultimers in heterologous systems.

3. Enormous diversity of Kv channel function arises from the multiplicity of subunits, the formation of heteromultimers within subfamilies and from association with intracellular β‐subunit proteins.

4. In the absence of direct structural information, mutational analyses have provided considerable insights into the structure of the voltage‐sensor, pore‐forming region and the sites of action of drugs, toxins and associated proteins.

5. Another subfamily, the inwardly rectifying, or KIR, family, appears to have arisen from a deletion of the first four membrane spanning regions of ancient Kv channels, changing gating properties from outward to inward rectification. These include the G‐protein gated inward rectifiers and Katp channels.
ACETYLCHOLINE RECEPTORS AND THE CYTOSKELETAL CONNECTION
Authors: Phillips William D.
Published: June 2007

1. The post‐synaptic membranes of neurons and muscle cells are characterized by clusters of transmitter receptors, the number and type of which help to determine synaptic efficacy. Here I briefly review what is known of the mechanism of clustering of nicotinic acetylcholine receptors (AChR) at neuromuscular synapses.

2. The extracellular protein agrin is thought to be secreted by the motor nerve terminal and trigger localized clustering of AChR in the post‐synaptic membrane of the skeletal muscle cell.

3. Binding of agrin to its receptor, α‐dystroglycan, is followed by rearrangements of the muscle membrane cytoskeleton with localized replacement of dystrophin by utrophin. It remains unclear how these changes relate to the clustering of AChR.

4. In separate studies, RAPsyn/43k protein, a protein associated with the inner face of the post‐synaptic membrane was shown to be able to cluster AChR and link them to the cytoskeleton when both proteins were co‐transfected into fibroblasts.

5. Mutational studies on RAPsyn identified putative binding domains for AChR and for the cytoskeleton within the RAPsyn primary structure. Targeted disruption of the RAPsyn gene in mice prevented post‐synaptic AChR clustering and led to neonatal lethality. Thus RAPsyn might be the final link in the pathway that leads to AChR immobilization in the post‐synaptic membrane.

6. The recent observation that active forms of agrin are not restricted to cholinergic regions of the brain suggests that analogous pathways may exist for clustering other receptor types.
SOME PHYSIOLOGICAL OUTCOMES OF RENIN GENE STUDIES
Authors: Moris Brian J.
Published: June 2007

1. The cloning of the renin gene has permitted studies of its physiological regulation, extrarenal expression and role in disease.

2. Marked modulation of renin mRNA concentration is seen in adrenal, heart and hypothalamus in response to sodium depletion and inhibition of A11 formation, as well as in models of renal and genetic hypertension in the rat.

3. One important outcome of studies of the promoter has been the discovery of a cyclic AMP‐responsive sequence.

4. Sequence variations have been detected in or near the renin gene and have been used as markers in studies of its role in cardiovascular disease aetiology.

5. In conclusion, molecular biology has, in the past decade, made a significant contribution to the understanding of renin physiology and pathophysiology.
EFFECTS OF GAMMA‐AMINOBUTYRIC ACID ON REGIONAL VASCULAR RESISTANCES OF CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Takemoto Yumi
Published: June 2007

1. The regional vascular effects of a central injection of gamma‐aminobutyric acid (GABA) in conscious spontaneously hypertensive rats (SHR) were compared with normotensive control rats (NCR), including Wistar‐Kyoto rats (male, 10–20 weeks of age). One week or more after insertion of a cannula into the cisterna magna, an electromagnetic flow probe was implanted around one of five arteries, and a catheter for measurement of blood pressure and heart rate was inserted into the terminal aorta or common carotid artery. Cardiovascular changes were observed in the conscious animal after recovery from the surgery. Peripheral resistance was calculated as pressure divided by flow.

2. Ten min following intracisternal injection of 10μmol of GABA, mean arterial pressure and heart rate were significantly lowered (P < 0.05; t‐test): ‐ 29 and ‐ 16% (70 d.f.) in SHR versus ‐ 23 (116 d.f.) and ‐19% (112 d.f.) in NCR. Hindquarters, carotid, superior mesenteric and renal, but not coeliac, vascular resistances were significantly lowered (P < 0.05; t‐test, 21, 9, 18 d.f.) in SHR. However, when comparing the effect of GABA injection in SHR and NCR, there were no significant differences in coeliac, carotid and hindquarters vascular resistances, but there were significant decreases in superior mesenteric and renal vascular resistances in SHR.

3. These results indicate that: (i) a cisternal injection of GABA in SHR decreases both peripheral vascular resistance and heart rate, and thereby lowers blood pressure; (ii) the vascular resistance of the superior mesenteric and renal vascular beds was more decreased in SHR than in NCR. This suggests that the GABAergic control of regional vascular resistance differs in the SHR and the NCR.
CORRELATION ANALYSIS OF BLOOD PRESSURE AND PLATELET AGGREGATION/VASCULAR REACTIVITY IN SHRSP, WKY, F1 AND BACKCROSS GENERATIONS
Authors: Hamano Megumi , Mashiko Satoshi , Onda Takeshi , Tomita Isao , Tomita Takako
Published: June 2007

1. Hypofunction of stroke‐prone spontaneously hypertensive rat (SHRSP) platelets at developmental ages of hypertension is due to the defective protein (p47) phosphorylation which is mediated by protein kinase C. This study was undertaken to examine the genetic association of platelet functions and vascular reactivity with hypertension using male WKY, SHRSP, F1 and backcross generations at 16–18 weeks of age.

2. The distribution of blood pressure was continuous in each generation.

3. Contraction of mesenteric vascular bed with norepin‐ephrine was positively correlated with blood pressure in the five generations (r = 0.77, n= 128).

4. Thrombin‐induced platelet aggregation was inversely correlated with blood pressure (r =−0.87, n= 127).

5. The distribution of platelet aggregation and contraction was continuous in each generation, and backcross generations were not likely to have 1:1 segregation.

6. These results suggest the possibility that platelet hypo‐aggregability and peripheral vascular resistance are due to the pleiotropic effect of hypertensive genes, or that genes controlling these three characters are closely linked each other.
CALCITONIN GENE‐RELATED PEPTIDE‐INDUCED RELAXATION IN ISOLATED SMALL SUPERIOR MESENTERIC ARTERIES FROM ADULT STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Gao Y. J. , Nishimura Y. , Suzuki A. , Nakai Y.
Published: June 2007

1. The relaxant responses to calcitonin gene‐related peptide (CGRP) of the 3rd order branches of the superior mesenteric arteries (SMA) from 6 month old stroke‐prone spontaneously hypertensive rats (SHRSP) and age‐matched Wistar‐Kyoto (WKY) rats were studied in vitro.

2. Cumulative addition of CGRP (10‐11‐10‐7 mol/L) caused endothelium‐independent relaxation of arterial rings precontracted with noradrenaline (10‐6 mol/L). A markedly increased response to CGRP was observed in SHRSP.

3. There was no significant difference between SHRSP and WKY in relaxation produced by forskolin, dibutyryl cyclic AMP and 3‐isobutyl‐1‐methylxanthine.

4. Pretreatment with glibenclamide (10‐6 mol/L) did not affect CGRP‐induced relaxation in either SHRSP or WKY.

5. These results indicated that CGRP‐induced vasodilation was increased in the small branches of SMA from SHRSP, and that this increase did not seem to be associated with an augmented response to cyclic AMP or with increased involvement of ATP‐sensitive potassium channels.
ALTERED SIGNALLING IN VASCULAR SMOOTH MUSCLE FROM SPONTANEOUSLY HYPERTENSIVE RATS MAY LINK MEDIAL HYPERTROPHY, VESSEL HYPERINNERVATION AND ELEVATED NERVE GROWTH FACTOR
Authors: Tuttle Jeremy B. , Spitsbergen John M. , Stewart Jeanine S. , McCarty Richard M. , Steers William D.
Published: June 2007

1. Secretion of nerve growth factor (NGF) by cultured vascular smooth muscle cells (VSMC) derived from spontaneously hypertensive rats (SHR) and the normotensive Wistar‐Kyoto (WKY) strain was measured via two site immuno‐assay (ELISA).

2. Basal NGF secretion rates of quiescent SHR VSMC in serum‐free culture medium were elevated compared to similar WKY VSMC.

3. SHR VSMC displayed increased NGF secretion in response to activation of sympathetic neurotransmitter receptors while VSMC of WKY were largely unresponsive to the agents (phenylephrine, isoproterenol, alpha‐beta‐methyl ATP, neuro‐peptide Y).

4. Mitogenic stimulation with platelet‐derived growth factor (PDGF) raised SHR NGF secretion rates almost three times more than PDGF increased WKY secretion.

5. SHR VSMC also failed to demonstrate normal inhibitory control over NGF secretion seen in WKY and previously in Sprague‐Dawley and Wistar strain VSMC with adenylate cyclase activation and down‐regulation of protein kinase C. High concentrations of forskolin stimulated, instead of inhibiting, secretion in SHR. Stimulation was also seen after pre‐treatment with phorbol ester for 24 h while this inhibited secretion in the WKY.

6. These results confirm that the SHR VSMC are hyper‐responsive to growth stimuli such as contractile agonists and mitogens. This hyperresponsiveness includes an abnormal control over NGF secretion such that normally inhibitory treatments stimulate NGF output in the SHR.

7. Because the SHR demonstrates important defects in the major intracellular growth‐signalling systems that also regulate NGF output and vessel innervation, the predicted result of the defects is a destructive feed‐forward cycle of growth and innervation. This is the SHR phenotype in vivo.