bluuebunny/crossref_metadata_2025 huggingface dataset:
LONG‐TERM EFFECTS OF HIGH CALORIE SUCROSE‐ENRICHED DIET AND STREPTOZOTOCIN‐INDUCED DIABETES ON INSULIN RESISTANCE IN SPONTANEOULY HYPERTENSIVE RATS§
Authors: Sato Toshiaki , Nara Yasuo , Kato Yuzuru , Yamori Yukio
Published: June 2007

1. The effects of two experimental manipulations on insulin resistance were compared in spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats. Rats were fed a high calorie sucrose‐enriched diet (high calorie diet) or were made diabetic by the injection of streptozotocin (STZ).

2. After treatment with the high calorie diet for 8 weeks, blood pressure increased in SHR, but not in WKY rats. In contrast, STZ treatment decreased blood pressure in SHR, but increased it in WKY rats.

3. Plasma glucose levels during oral glucose loading were higher in SHR than in WKY rats. Glucose tolerance was impaired to a greater extent by both the high calorie diet and STZ in SHR than in WKY rats. Hyperinsulinaemia induced by the high calorie diet was severe in SHR compared with WKY rats.

4. Abnormalities in lipid metabolism induced by a high calorie diet or STZ‐induced diabetes were more marked in SHR than in WKY rats.

5. Steady‐state plasma glucose levels in the insulin suppression test were higher in SHR than in WKY rats, both of which were treated by either the high calorie diet or STZ. These findings indicate that insulin‐stimulated glucose uptake by high calorie diet or STZ‐induced diabetes was impaired to a greater extent in SHR than in WKY rats.

6. It is concluded, therefore, that SHR fed on high calorie diet or SHR with STZ‐induced diabetes are suitable models to study the effects of antihypertensive treatment on glucose tolerance, insulin resistance or lipid metabolism as well as blood pressure.
NEURAL CONTROL OF THE CIRCULATION IN HEART FAILURE AND CORONARY ISCHAEMIA: INTRODUCTION
Authors: Zucker Irving H.
Published: June 2007

1. A large gap in our knowledge of the reflex control of the circulation still exits in the setting of chronic heart failure. This symposium will provide state‐of‐the‐art experimental data on the reflex regulation of the circulation in heart failure and myocardial ischaemia.

2. Alterations in arterial baroreflex and cardiopulmonary reflexes contribute to the increase in sympathetic tone in this disease state. Additionally, changes in neurohormones, such as angiotensin, are thought to contribute.

3. Coronary ischaemia is associated with activation of both vagal and sympathetic reflexes of cardiac origin. The balance between activation of these two reflexes will determine the ultimate change in sympathetic outflow.

4. Sensory endings in the myocardium are exquisitely sensitive to local mediators, such as prostaglandins, oxygenderived free radicals, adenosine and bradykinin.
β‐ADRENOCEPTOR DESENSITIZATION DURING THE DEVELOPMENT OF CANINE PACING‐INDUCED HEART FAILURE
Authors: Vatner Dorothy E. , Sato Naoki , Ishikawa Yoshihiro , Kiuchi Kaname , Shannon Richard P. , Vanter Stephen F.
Published: June 2007

1. The goal of this review is to emphasize four major points regarding the development of catecholamine desensitization in heart failure (HF).

2. Catecholamine desensitization occurs prior to the development of HF (i.e. after 1 day of rapid pacing, physiological responses to β‐adrenoceptor stimulation are depressed by over 50%, yet no evidence of HF is observed for 3‐4 weeks of rapid pacing).

3. Multiple mechanisms in the β‐adrenoceptor cascade are involved. In HF there are decreases in β1‐adrenoceptors, high affinity β‐adrenoceptors, adenylyl cyclase activity and messenger RNA and increases in Gi.

4. Not all mechanisms appear simultaneously (i.e. early decreases occur in high affinity β‐adrenoceptors and adenylyl cyclase; late increases in Gi and decreases in β‐adrenoceptor density evolves).

5. Mechanisms distal to cAMP generation also play a role (i.e. alterations in ryanodine receptor binding and excitationcontraction coupling also occur).
NEURAL RESPONSES TO EXERCISE IN HUMANS: IMPLICATIONS FOR CONGESTIVE HEART FAILURE
Authors: Sinoway Lawrence I.
Published: June 2007

1. During static handgrip exercise, muscle metaboreceptors are stimulated, evoking the ‘exercise pressor reflex'. As part of this reflex, sympathetic discharge to skeletal muscle is increased. The muscle ‘metaboreceptors’ are thought to be free nerve endings of unmyelinated group IV nerve fibres. These receptors are stimulated by a number of metabolites, including lactic acid, H+, diprotonated phosphate, adenosine and the biproducts of prostaglandin synthesis.

2. During chronic, repetitive activity, muscle metabolitesensitive afferents may be desensitized. We speculate that metaboreceptor desensitization also occurs in congestive heart failure (HF). Despite this desensitization, sympathoexcitatory responses to forearm exercise are preserved. This suggests that some other neural system aside from muscle metaboreceptors must be activated to a greater degree in HF. We speculate that in HF the activity of muscle mechanoreceptors is increased. Furthermore, we believe that limb congestion can increase the discharge of muscle mechanoreceptors, thereby evoking nonmetaboreceptor‐mediated increases in sympathetic discharge. Future studies in our laboratory will examine the role limb congestion and decongestion play in evoking muscle mechanoreceptor‐mediated sympathoexcitatory responses.
REFLEXES MEDIATED BY CARDIAC SYMPATHETIC AFFERENTS DURING MYOCARDIAL ISCHAEMIA: ROLE OF ADENOSINE
Authors: Thames Marc D. , Dibner‐Dunlap Mark E. , Minisi Anthony J. , Kinugawa Toru
Published: June 2007

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano‐ or chemosensitive, whereas sympathetic afferents may be mechano‐, chemosensitive or both.

2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses.

3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate.

4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A1, but not adenosine A2 receptors.

5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.
ANTIHYPERTENSIVE EFFECTS OF dl‐ TETRAHYDROPALMATINE: AN ACTIVE PRINCIPLE ISOLATED FROM CORYDALIS
Authors: Lin MT , Chueh FY , Hsieh MT , Chen CF
Published: June 2007

1. The effects of dl‐tetrahydropalmatine (dl‐THP) on cardiovascular function and hypothalamic release of monomines were assessed in rats under urethane anaesthesia.

2. Intravenous administration of dl‐THP (1‐10 mg/kg) produced hypotension, bradycardia, a decrease in hypothalamic serotonin and noradrenaline release and in increase in hypothalamic dopamine release in rats.

3. Intrahypothalamic administration of DOI (a serotonergic 5‐HT2 receptor antagonist) or apomorphine (a dopamine D2‐receptor agonist) produced the opposite effects and reversed dl‐THP‐induced hypotension and bradycardia.

4. The data suggest that dl‐THP acts through the 5‐HT2 and/or D2‐receptor antagonism in the hypothalamus to induce hypotension and bradycardia in rats.
A FAMILY OF NOVEL ACTIN‐INHIBITING MARINE TOXINS
Authors: Saito Shin‐ya , Karaki Hideaki
Published: June 2007

1. We have examined the effects of marine toxins with a macrolide structure on actin. These toxins include mycalolide B, aplyronine A and bistheonellide A.

2. Measuring actin polymerization by monitoring fluorescent intensity of pyrenyl‐actin, mycalolide B did not accelerate the actin polymerization but quickly depolymerized F‐actin. In contrast, cytochalasin D, which inhibits actin polymerization by binding to the barbed end of F‐actin, accelerated actin nucleation and depolymerized F‐actin at a slower rate.

3. Analysing the kinetics of depolymerization by monitoring the rate of spontaneous depolymerization of F‐actin under the unpolymerizable state or the rate of polymerization where F‐actin was seeded as a nucleus, mycalolide B was suggested to sever F‐actin.

4. The relationship between the concentration of total actin and F‐actin at different concentrations of mycalolide B suggests that mycalolide B forms a 1:1 complex with G‐actin. Viscometry and electron microscopic observations further suggest that the actin filament was depolymerized by mycalolide B. Furthermore, mycalolide B suppressed actin‐activated myosin Mg2+‐ATPase activity, although cytochalasin D did not. Aplyronine A has similar effects on actin.

5. Bistheonellide A also depolymerized F‐actin and sequestered G‐actin by forming a 1:2 complex with G‐actins, but, its severing effect was not detected. We conclude that mycalolide B, aplyronine A and bistheonellide A are novel types of actin‐depolymerizing agents, the mechanism of action of which is different from that of cytochalasin D. These structurally related marine toxins may be categorized as ‘actin depolymerizing macrolides’ and may serve as novel pharmacological tools for analysing actin‐mediated cell functions.
TETRANDRINE AS A CALCIUM ANTAGONIST
Authors: Takemura Haruo , Imoto Kenshi , Ohshika Hideyo , Kwan Chiu‐Yin
Published: June 2007

1. The Ca2+‐antagonism of tetrandrine (TET) on the Ca2+ mobilization in various types of cells were reviewed. Inositol trisphosphate (IP3)‐generating drugs were used as Ca2+‐mobilizing agonists and the effects were compared with those produced by using the microsomal Ca2+‐ATPase inhibitor thapsigargin (TG), which is a tool for analysing Ca2+ which is a tool for analysing Ca2+ store ‐regulated Ca2+ entry (capacitative Ca2+ entry).

2. In rat phaeochromocytoma PC12 cells, 100 μmol/L TET abolished high K+ (30 mmol/L)‐induced sustained increases in cytoplasmic Ca2+ concentrations ([Ca2+]i) and partially inhibited bradykinin (1 μmol/L)‐ or TG (100 nmol/L)‐induced Ca2+ entry.

3. In NIH/3T3 fibroblasts and rat parotid acinar cells, 100 μmol/L TET abolished Ca2+ entry induced by bombesin (1 μmol/L) and carbachol (100 μmol/L), respectively, or TG (100 nmol/L). However, in the human leukaemia T cell line Jurkat, 100 μmol/L TET did not inhibit Ca2+ entry evoked by either the anti‐CD3 antibody OKT3 (10 mg/L) or TG (100 nmol/L).

4. In rat glioma C6 cells, the effects of TET on Ca2+ mobilization were further examined. At a high concentration, TET (300 μmol/L) alone did not affect [Ca2+]i in C6 cells. Tetrandrine inhibited the peak and sustained increases in [Ca2+]i induced by bombesin and TG in a dose‐dependent manner. Although TET or TG did not produce increases in IP3, TET did inhibit increases in IP3 produced by bombesin.

5. Our results suggest that the action of TET on Ca2+ entry is dependent on cell types and that TET inhibits both Ca2+ entry from the extracellular medium and Ca2+ release from intracellular stores in rat glioma C6 cells.
PLASMA FOLLISTATIN CONCENTRATIONS INCREASE FOLLOWING LIPOPOLYSACCHARIDE ADMINISTRATION IN SHEEP
Authors: Klein Rudi , Clarke Iain J. , Hedger Mark P. , Robertson David M.
Published: June 2007

1. The effect of inflammation induced by lipopolysaccharide (LPS) injection on plasma follistatin (FS) concentrations was investigated.

2. Plasma FS and tumour necrosis factor‐α concentrations increase following LPS administration in ewes.

3. The rise in FS is similar, but more sustained, to that previously observed after surgery.

4. These results indicate a possible functional link between FS, inflammation and the acute‐phase response.
EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP
Authors: Stevenson Kathleen M. , Gibson Karen J. , Lumbers Eugenie R.
Published: June 2007

1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change.

2. Fetal haematocrit increased (P < 0.05), fetal PO2 decreased (P < 0.01), PCO2 did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis.

3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan.

4. It is concluded that the fetal renin‐angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.
REGULATION AND INTERACTIONS OF TRANSFORMING GROWTH FACTOR‐β WITH CARDIOVASCULAR CELLS: IMPLICATIONS FOR DEVELOPMENT AND DISEASE
Authors: Saltis John , Agrotis Alex , Bobik Alex
Published: June 2007

1. Transforming growth factors‐β (TGF‐β) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling.

2. The diverse biological actions of TGF‐β are elicited following their interaction with type I and type II TGF‐β receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment.

3. Alterations in TGF‐β gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.
EFFECTS OF DC‐015, A NOVEL POTENT AND SELECTIVE α1‐ADRENOCEPTOR ANTAGONIST ON PLASMA LIPID AND VASCULAR REACTIVITY IN HYPERLIPIDAEMIC RATS
Authors: Sheu Joen‐Rong , Peng I‐Hsun , Lee Yen‐Mei , Yen Mao‐Hsiung
Published: June 2007

1. The effects of DC‐015, a newly synthesized quinazoline derivative, on plasma lipids, lipoprotein levels and vascular reactivity were investigated in Wistar‐Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).

2. The hypotensive effect of DC‐015 was compared with prazosin in SHR. Intravenous administration of DC‐015 and prazosin (both at 0.01, 0.05 and 0.1mg/kg) induced dose‐dependent reductions in mean arterial pressure (MAP) which reached a maximal effect 5 min after injection and persisted over 2 h in SHR. DC‐015 decreased MAP with equal efficiency compared with prazosin.

3. The plasma levels of total cholesterol (CE), low‐density lipoprotein (LDL)‐CE and total triglyceride (TG) were markedly increased and the levels of high‐density lipoprotein (HDL)‐CE were markedly decreased in both high fat‐high cholesterol (HF‐HC) diet fed WKY and SHR.

4. In HF‐HC diet fed WKY and SHR, the total plasma CE, LDL‐CE and total plasma TG were significantly reduced after oral administration of DC‐015 (1 mg/kg, twice a day) for 4 weeks. Furthermore, DC‐015 therapy was associated with increased HDL‐CE levels and thus the ratio of total CE to HDL‐CE was improved. The antihyperlipidaemic effect of prazosin was less than that of DC‐015.

5. Significantly attenuated median effective concentration (EC50) values and augmented maximal responses for phenyl‐ephrine‐induced contraction of aortic rings were observed in HF‐HC diet fed WKY and SHR. Endothelium‐dependent relaxation to acetylcholine was impaired while endothelium‐independent relaxation to nitroglycerin was well preserved.

6. Oral administration of DC‐015 (1 mg/kg, twice a day) for 4 weeks significantly augmented EC50 values and attenuated maximal responses for phenylephrine‐induced contraction of aortic rings in HF‐HC diet fed WKY and SHR. Prazosin (1 mg/kg, twice a day) showed a lesser extent of efficiency than DC‐015 at normalization of vasorelaxation in HF‐HC diet fed WKY and SHR.

7. It is concluded that DC‐015, a potent antihypertensive agent, may have additional advantage in also reducing hyperlipidaemia.
EFFECT OF THE HYDROXYL RADICAL ON FIBROBLAST‐MEDIATED COLLAGEN REMODELLING IN VITRO
Authors: Arisawa Shoko , Arisawa Tomiyasu , Ohashi Masaru , Nitta Yukiko , Ikeya Toshihiko , Asai Junpei
Published: June 2007

1. It has been reported that free radicals prevent wound healing. However, the mechanism of this effect is not yet clear. We attempted to clarify the influence of hydroxyl radicals on wound healing in vitro.

2. We used an ascorbate‐copper ion system (ACS) to produce hydroxyl radicals in accordance with variables of time elapsed and concentration of copper ion. The effects of hydroxyl radical on fibroblast‐mediated collagen remodelling, cell viability, the functions of fibroblasts and collagen fibrils were studied.

3. With a copper ion concentration of 100μmol/L ACS significantly reduced contraction, while 10μmol/L stimulated contraction. Hydrogen peroxide (H2O2) was employed in observing these findings. ACS did not influence cell viability, the expression of α2β1 integrin and cellular fibronectin, or the cytoskeletal organization of fibroblasts involving actin until 3h. A concentration of ACS at 10μmol/L of copper ion induced the polymerization of collagen after 30 min, while ACS at 100 μmol/L induced collagen degradation; this finding was also established by using H2O2. Collagen reduced the amount of formaldehyde produced by trapping hydroxyl radical with dimethyl sulfoxide.

4. Our findings suggest that collagen is denatured by scavenging the hydroxyl radical before fibroblasts are damaged, so that the radical may influence the remodelling of collagen.
PROTECTIVE EFFECTS OF ME3221 ON HYPERTENSIVE COMPLICATIONS AND LIFESPAN IN SALT‐LOADED STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nagura Jun , Yamamoto Mikio , Hui Chen , Yasuda Sumie , Hachisu Mitsugu , Konno Fukio
Published: June 2007

1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT1 receptor antagonist; losartan, in which a major active metabolite is a non‐competitive angiotensin AT1 receptor antagonist; and enalapril, an angiotensin‐converting enzyme inhibitor, using the salt‐loaded stroke‐prone spontaneously hypertensive rats (SHRSP).

2. SHRSP received orally ME3221 (3 and 10mg/kg per day), losartan (10mg/kg per day) and enalapril (10mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age.

3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt‐loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to >90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N‐acetyl‐β‐D‐glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion).

4. Competitive (ME3221) and non‐competitive (losartan) angiotensin AT1 receptor antagonists showed comparable efficacy against the complications and mortality of the salt‐loaded SHRSP; both were more potent than enalapril in the protective effect.
SUPPRESSIVE EFFECTS OF A HERBAL FORMULA, TBL‐1, ON TYPE II COLLAGEN‐INDUCED ARTHRITIS IN DBA/1J MICE
Authors: Li Song‐Hua , Kobayashi Yuta , Yamauchi Yasutaka , Gonda Tatsuo , Tsunematsu Tokugoro
Published: June 2007

1. The effects of a formula of traditional Chinese medicine, TBL‐1, on collagen‐induced arthritis (CIA) were investigated in DBA/1J mice.

2. From 4 weeks after the first immunization with bovine type II collagen (CII), TBL‐1 or indomethacin was administered orally for 13 weeks.

3. Clinical scores of CIA were decreased by both TBL‐1 and indomethacin intervention compared with the control CII‐immunized group.

4. Radiographic scores of phalangeal destruction were markedly improved by TBL‐1 intervention (P<0.001), but indomethacin failed.

5. The suppressive effects of TBL‐1, but not indomethacin, were manifested in reduced serum anti‐CII antibody titres (P<0.001).

6. These findings suggest that TBL‐1 may play a role in regulating some immune responses in the present arthritis model.
REGULATION OF EXPRESSION OF THE ENDOTHELIAL CELL NITRIC OXIDE SYNTHASE
Authors: Harrison David G. , Sayegh Hassan , Ohara Yuichi , Inoue Nobutaka , Venema Richard C.
Published: June 2007

1. Recent studies have provided insight into how the expression of endothelial cell nitric oxide synthase (ecNOS) is regulated.

2. The promoter of ecNOS has several features that are compatible with a constitutively expressed, so‐called ‘house keeping’ gene. These include absence of a TATA box and the presence of Sp1 binding sites located near the transcription start site. The promoter also contains a number of putative binding domains which suggests that it may be regulated by a variety of transcription factor mediated signals.

3. Studies of cultured endothelial cells suggest that ecNOS expression is modulated by shear stress, transforming growth factor beta, inhibition of protein kinase C and the state of proliferation. These experiments indicate that although the ecNOS is a ‘constitutively expressed’ gene, its content in the endothelium is subject to modest degrees of regulation that may have important physiological and pathophysiological implications.
VASCULAR REMODELLING AND MOLECULAR BIOLOGY: NEW CONCEPTS AND THERAPEUTIC POSSIBILITIES
Authors: Agrotis Alex , Bobik Alex
Published: June 2007

1. Over the past decade major advances in molecular cell biology have greatly increased our understanding of the way in which many growth factor genes are expressed and regulated. This knowledge is currently being translated into investigations of the cardiovascular system.

2. Two growth factor families appear to play particularly important roles, the fibroblast growth factors and the transforming growth factors‐β. These are multifunctional growth factors capable of remodelling the vasculature through their effects on cell migration, proliferation and matrix formation.

3. An understanding of their regulation, properties and nature of their receptors is providing novel insights into the physiology and pathobiology of the vasculature. It is also providing highly specific targets for future therapy.
SODIUM STATUS, CORTICOSTEROID METABOLISM AND BLOOD PRESSURE IN NORMAL HUMAN SUBJECTS AND IN A PATIENT WITH ABNORMAL SALT APPETITE
Authors: Ingram Mary C , Wallace A Michael , Collier Andrew , Fraser Robert , McConnell John
Published: June 2007

1. A patient with severe hypertension was found to have mildly impaired 11β‐hydroxysteroid dehydrogenase (11β‐HSD) activity on the basis of urinary steroid metabolite ratios, low plasma aldosterone, angiotensin II and renin levels and marginally low levels of plasma potassium.

2. The patient also had a compulsively high salt intake.

3. We tested the hypothesis that high salt intake may affect 11β‐HSD activity.

4. High salt intake in normal subjects did not significantly alter either blood pressure or 11β‐HSD activity.

5. We suggest that the potentially small hypertensive effect of the partial enzyme deficiency in our patient, also reported in patients with essential hypertension, has been markedly amplified by the very high salt intake.
RELATIONSHIP OF CIGARETTE SMOKING TO BLOOD PRESSURE AND SERUM LIPIDS AND LIPOPROTEINS IN MEN
Authors: Imamura Hiroyuki , Tanaka Keiko , Hirae Chinatsu , Futagami Tomomi , Yoshimura Yoshitaka , Uchida Kazuhiro , Tanaka Ayumi , Kobata Daikichi
Published: June 2007

1. The relationship of cigarette smoking to blood pressure and serum lipids and lipoproteins was studied in 7608 men, ranging from 40 to 59 years of age. Analyses were performed separately for non‐drinkers and drinkers.

2. After adjusting age and body mass index (BMI) in non‐drinkers and age, BMI and alcohol intake in drinkers in forward stepwise multiple regression analysis, there was a dose‐dependent negative relationship between cigarette smoking and diastolic blood pressure (DBP) and high density lipoprotein cholesterol (HDL‐C), regardless of drinking habit. There was a dose‐dependent positive relationship between cigarette smoking and the ratio of total cholesterol (TC) to HDL‐C (TC:HDL‐C) in non‐drinkers, but not in drinkers. There was a dose‐dependent negative relationship between cigarette smoking and TC and a positive relationship between cigarette smoking and triglycerides (TG) in drinkers, but not in non‐drinkers.

3. After matching age and BMI in non‐drinkers, subjects who smoked more than 30 cigarettes/day had significantly lower mean values of systolic blood pressure (SBP; 4.3%; P<0.05), DBP (3.0%;P<0.01) and HDL‐C (15.5%;P<0.01) and higher mean values of TC:HDL‐C (25.0%;P<0.01), TG (46.8%; P<0.01) and β‐lipoprotein (12.0%; P<0.01) than non‐smokers. In drinkers, after matching age, BMI, and alcohol intake, subjects who smoked more than 30 cigarettes/day had significantly lower mean values of SBP (2.8%; P<0.05), DBP (4.8%; P<0.01), HDL‐C (17.3%; P<0.01) and TC (4.4%; P<0.01) and higher mean values of TC:HDL‐C (15.4%; P<0.01) and TG (45.1%;P<0.01) than non‐smokers.

4. Although the results are somewhat variable, the present study reveals that cigarette smoking is negatively associated with SBP and DBP and unfavourably associated with lipids and lipoproteins, regardless of drinking habit.
BLOOD PRESSURE LOWERING IN PATIENTS WITH CEREBROVASCULAR DISEASE: RESULTS OF THE PROGRESS (PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY) PILOT PHASE
Authors: Neal Bruce , Anderson Craig , Chalmers John , MacMahon Stephen , Rodgers Anthony , Committee PROGRESS Management
Published: June 2007

1. Among patients with cerebrovascular disease, there is a direct and continuous association between blood pressure and the risk of stroke, but previous trials of blood pressure lowering in this patient group have been inconclusive.

2. PROGRESS (Perindopril Protection Against Recurrent Stroke Study) is a multicentre, randomized, placebo‐controlled trial that aims to determine reliably the effect of angiotensin converting enzyme (ACE) inhibitor‐based blood pressure lowering on stroke risk in patients with a history of cerebrovascular disease. If a 4 week run‐in period on active perindopril is well tolerated, participants are randomized to either perindopril (4 mg) ± indapamide (2.5 mg) or matching placebo(s). The primary study outcome is stroke and follow‐up is for a minimum of 4 years.

3. For the pilot study nearly 5000 medical records were screened and 60 patients with recent cerebrovascular events were approached directly in hospital or at a clinic visit. Sixtyseven patients entered the run‐in phase (52 from retrospective screening and 15 by prospective approach) and 60 patients proceeded to randomization. Treatment with perindopril was well tolerated; only three patients were withdrawn due to side effects and four were withdrawn for other reasons. The mean age of randomized patients was 68 years; 70% were male and 55% were ‘non‐hypertensive'. The mean entry blood pressure was 142/83 mmHg and following pre‐randomization treatment this was reduced by 7/4 mmHg.

4. Most patients were identified by retrospective review of medical records, but this was less efficient than prospective methods. Blood pressure lowering was well tolerated by both hypertensive and non‐hypertensive patients with cerebrovascular disease. The small numbers of patients and the nonrandomized nature of the data reported limit the conclusions that can be drawn, but the results confirm the feasibility of the main study.
RECENT INSIGHTS INTO THE REGULATION OF CEREBRAL CIRCULATION
Authors: Brian Johnny E , Faraci Frank M , Heistad Donald D
Published: June 2007

1. Mechanisms that regulate the cerebral circulation have been intensively investigated in recent years. The role of several vasodilator mechanisms has been examined in the cerebral circulation, including nitric oxide (NO), trigeminal peptides and potassium channels, as well as the potent vasoconstrictor endothelin. These mediators appear to play a role in physiological and pathophysiological responses of the cerebral circulation. In the present review, we will focus on some recent developments in each of these areas.

2. Nitric oxide is an important regulator of cerebral vascular tone. Tonic production of NO maintains the cerebral vasculature in a dilated state. NO appears to be an important vasodilator during activation of neurons by excitatory amino acids, somatosensory stimulation and cortical spreading depression. Tonic production of NO appears to be critical in vasodilatation during hypercapnia, although NO may not directly mediate vasodilatation. NO produced by immunological NO‐synthase appears to be important in dilatation following exposure to bacterial endotoxin.

3. Calcitonin gene‐related peptide (CGRP), released from trigeminal perivascular sensory nerves in the brain, is an extremely potent dilator of brain vessels. CGRP may limit noradrenaline‐induced constriction of cerebral vessels and contribute to dilatation during hypotension (autoregulation), reactive hyperaemia, seizures and cortical spreading depression.

4. Activation of potassium channels leads to hyperpolarization of cerebral vascular smooth muscle and appears to be a major mechanism for dilatation of cerebral arteries. Agents that increase the intracellular concentration of cyclic 3′ 5′‐adenosine monophosphate (cAMP) produce vasodilatation in part by activation of large conductance calcium‐activated potassium channels (BKCa) and ATP‐sensitive potassium channels (KATP). Activation of both KATP and BKCa channels also appears to contribute to vasodilatation during hypoxia. In contrast to KATP channels, BKCa channels appears to be active under basal conditions, contributing to tonic dilatation of cerebral blood vessels.

5. Endothelin is produced in the brain, but its role in the physiological regulation of cerebral blood flow is not known. Endothelin may contribute to the spasm of cerebral arteries following subarachnoid haemorrhage.
SPONTANEOUS AND AGONIST‐INDUCED CONTRACTIONS AND ENDOTHELIUM‐DEPENDENT RELAXATION IN AORTAE FROM SHRSP AND WKY RATS UNDER VARIOUS LEVELS OF PASSIVE FORCE
Authors: Sekiguchi Fumiko , Adachi Tomoko , Matsubara Hideki , Matsuda Kyoko , Kita Katsuhiro , Shimamura Keiichi , Sunano Satoru
Published: June 2007

1. The influence of the passive force on the contraction and endothelium‐dependent relaxation in aortae of normotensive Wistar Kyoto (WKY) rats and stroke‐prone spontaneously hypertensive rats (SHRSP) were compared.

2. Force changes of endothelium‐intact and ‐removed preparations were measured isometrically by a force‐displacement transducer. Endothelium‐dependent relaxation was observed by applying acetylcholine to the preparation precontracted in the presence of 5×10−7mol/L noradrenaline.

3. The preparations showed spontaneously developed tension (tone) that increased with the increase in the passive force. The effect of passive force was greater in preparations from SHRSP. Contraction initiated by noradrenaline was also increased by passive force up to 30 mN, then showed a tendency to decrease.

4. Endothelium‐dependent relaxation was depressed as the passive force was increased. Preparations from SHRSP showed impaired endothelium‐dependent relaxation and were influenced by passive force to a lesser degree when compared with preparations from WKY rats.

5. Relaxation by sodium nitroprusside was influenced by passive force to a much lesser extent than that by acetylcholine.

6. Indomethacin potentiated endothelium‐dependent relaxation and blocked the effect of passive force in both preparations.

7. The difference in relaxation and the effect of passive force is primarily caused by the difference in the release of endo‐thelium‐derived contracting factor, which is thought to be a product of the cyclo‐oxygenase pathway of the arachidonic acid cascade.
DOWN‐REGULATION OF ANGIOTENSIN II RECEPTORS IN HYPERTROPHIED HUMAN MYOCARDIUM
Authors: Nozawa Yoshihisa , Miyake Hidekazu , Haruno Akihiro , Yamada Shizuo , Uchida Shinya , Ohkura Takashi , Kimura Ryohei , Suzuki Harumi , Hoshino Tsuneo
Published: June 2007

1. Specific [125I]‐angiotensin II (AngII) binding in normal and hypertrophied human myocardial membranes was saturable and of high affinity. Low concentrations of unlabelled AngII and saralasin competed with [125I]‐AngII for the binding sites in these tissues. Thus, saturable [125I]‐AngII binding in human myocardium exhibited pharmacological specificity that characterized high affinity receptors for AngII.

2. There was little difference in the apparent dissociation constant (Kd) values for [125I]‐AngII binding between normal and hypertrophied human myocardium, whereas the maximal number of binding sites (Bmax) was significantly (51%) lower in the hypertrophied group. Further, PD123177, a selective antagonist of the AT2 receptor subtype, showed three orders of magnitude higher affinity for [125I]‐AngII binding sites in both normal and hypertrophied myocardium than losartan, a selective antagonist of the AT1 receptor subtype; the Hill coefficients for these drugs were close to one.

3. A significant decrease in Bmax and Kd values for (—)‐[125I]‐iodocyanopindolol binding between normal and hypertrophied human myocardium rarely occurred.

4. The present study suggests that both normal and hypertrophied human myocardium predominantly contains the AT2 receptor subtype and that these receptors are down‐regulated in hypertrophied tissues.
OESTROGEN RECEPTORS AND CARDIOVASCULAR DISEASE*
Authors: Baysal Kemal , Losordo Douglas W
Published: June 2007

1. Animal and human studies indicate that female sex hormones are protective against the development of coronary atherosclerosis.

2. Experiments on vascular smooth muscle cells suggest a direct effect of oestrogen on vascular tissue. Although oestrogen receptors (ER) in vascular tissues and an association between ER stimulation and physiological effects have been demonstrated, the cellular mechanisms underlying the effects of oestrogen on the arterial wall remain to be defined.

3. Elucidation of the cellular mechanism underlying the effects of oestrogen on vascular smooth muscle will provide insights into coronary atherosclerosis and will provide an opportunity to apply the protective effects of oestrogen to women in older age groups and to the male population.
VASCULAR LOCALIZATION OF THE 11β‐HYDROXYSTEROID DEHYDROGENASE TYPE II ENZYME
Authors: Smith Robin E , Little Peter J , Maguire Julie A , Stein‐Oakley Alicia N , Krozowski Zygmunt S
Published: June 2007

1. The enzyme 11β‐hydroxysteroid dehydrogenase type II (11βHSD2) confers specificity on the non‐specific mineralocorticoid receptor by converting cortisol to cortisone.

2. We have examined the localization of this enzyme in the human skin, myocardium and saphenous vein by immuno‐histochemical techniques.

3. High amounts of 11βHSD2 immunoreactivity were found in smooth muscle cells in the arterioles of the skin, heart and saphenous vein. Lower amounts of staining were also found in longitudinal and concentric smooth muscle cells lining the lumen of the saphenous vein.
DETERMINANTS OF CHANGE IN BLOOD PRESSURE DURING S.W.E.A.T.: THE SEDENTARY WOMEN EXERCISE ADHERENCE TRIAL
Authors: Cox Kay L , Puddey Ian B , Burke Valerie , Beilin Lawrence J , Morton Alan R , Bettridge Helen F
Published: June 2007

1. In a long‐term study of the optimal approach to initiating and maintaining a regular exercise programme in previously sedentary older women (40–65 years), we have assessed determinants of change in resting blood pressure (BP) after 6 and 12 months.

2. Women (n≈ 126) were randomly assigned to either a centre‐based or home‐based exercise programme for an initial 6 months. The centre‐based group attended supervised sessions three times per week, while the home‐based group exercised unsupervised at home three times per week. Both groups were home‐based during a second 6 months. Within each arm, subjects were further randomized to either exercise at moderate intensity (40–55% heart rate reserve; HRres) or at vigorous intensity (65–80% HRres). A nonintervention comparison group of 30 women was followed throughout.

3. At 6 months there was a fall in BP with moderate, but not vigorous intensity exercise (‐ 2.7 mmHg; P= 0.025), an effect no longer significant at 12 months.

4. Change in BP was unrelated to improvements in fitness (VO2max), increases in lean tissue mass, number of exercise sessions completed or a composite measure of the total number of exercise sessions completed multiplied by the mean exercise intensity expressed as a percentage of heart rate reserve (%HRres).

5. Continuing participation in any regular exercise was a consistent predictor of change in BP, with those subjects still exercising in the 2 weeks before BP measurement having 1.9 mmHg lower BP at 6 months (P= 0.038) and 3.8 mmHg lower BP at 12 months (P= 0.016).

6. We conclude that the small effects of exercise on resting BP in these older women are predominantly related to continuing participation in lower intensity exercise, rather than to improvements in fitness or body composition.
REMODELLING OF RESISTANCE ARTERIES IN GENETICALLY HYPERTENSIVE RATS BY TREATMENT WITH VALSARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST
Authors: Ledingham Janet M , Laverty R.
Published: June 2007

1. In the present study, New Zealand genetically hypertensive (GH) rats were treated with valsartan, a specific angiotensin II (AT1) receptor antagonist, to measure the effects on blood pressure (BP), cardiac hypertrophy and the structure of resistance arteries. Normotensive (N) rats were used as controls.

2. Valsartan (val) was given to GH rats at three different doses (10, 3 or 0.3 mg/kg per day, via osmotic mini‐pumps implanted i.p.) from age 4–10 weeks. Untreated GH (mini‐pump + vehicle) and N rats (mini‐pump + vehicle) were used as controls. BP was measured weekly and at the end of the experiment, left ventricular (LV) mass was recorded and the structure of mesenteric resistance arteries (MRA) was determined using stereological methods.

3. BP fell in a dose‐dependent fashion, being reduced to normotensive levels by 10 mg/kg; LV mass was significantly reduced (P > 0.0001) to below normotensive values in the GH group given 10 mg/kg val and significantly reduced (P > 0.001), although not normalized, in the other two treatment groups.

4. In MRA, the media/lumen (M/L) ratio was reduced by val according to dose level, to below normotensive values in GHval10, and to levels not different from normotensive values in the GHva13 and GHva10.3 groups.

5. The hypertrophy of smooth muscle cells in GH rats was reduced with val treatment at all doses.

6. Reversal of cardiac and vascular hypertrophy occurred even when BP was not reduced to normotensive levels, indicating an effect on vessel growth but without any retardation of body growth.

7. These results suggest that the vascular structural changes seen after val and angiotensin converting enzyme inhibitor treatment are probably due to the blocking of angiotensin rather than any bradykinin effect.
PCR‐SSCP ANALYSIS OF THE p53 GENE IN TUMOURS OF THE ADRENAL GLAND
Authors: Ballantine DM , Klemm SA , Tunny TJ , Stowasser M. , Gordon RD
Published: June 2007

1. Mutations of the p53 tumour suppressor gene are relatively common in the aetiology of a wide spectrum of tumour types, both sporadic and familial.

2. The majority of mutations of the p53 gene are reported to be in the highly conserved region of exons 5–8.

3. Alterations in exons 4, 5 and 7 of the p53 gene in patients with functional adrenal tumours, including aldosterone‐producing adenomas, have recently been described.

4. In the present study PCR‐SSCP was used to examine the exons 4–9 of the p53 gene in paired peripheral blood leucocyte and tumour DNA in a variety of adrenal tumours, including aldosterone‐producing carcinoma and adenoma (both familial and sporadic), phaeochromocytoma and incidentaloma.

5. No evidence was found for mutations in exons 4–9 of the p53 gene in these varieties of adrenal tumours.
ANALYSIS OF LINKAGE OF THE ACE LOCUS WITH MEASURES OF CARDIAC HYPERTROPHY IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Zhang L. , Summers KM , West MJ
Published: June 2007

1. The effects of genetic factors on cardiac myocyte diameter and other phenotypes of heart size were determined in genetically hypertensive rats. Direct blood pressure, heartweight and cardiac myocyte size were measured at 12 weeks of age in spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats and F2 males derived from these rats. The genotypes of the angiotensin converting enzyme (ACE) gene on rat chromosome 10 were determined by amplification of DNA using the polymerase chain reaction in F2 animals and were correlated with measures of phenotypes using anova and t‐test.

2. Significant correlations between fibre diameter and myocytes and heartweight or left ventricular weight were observed in SHR, WKY and F2 males. There was no correlation of myocyte size with systolic blood pressure in F2 rats. ACE genotype was weakly correlated with heartweight, but not correlated with myocardial fibre diameter in F2 males, suggesting that this gene may primarily cause expansion of extracellular tissue rather than cardiac myocyte size.

3. Genetic factors may influence heart size through effects on the cardiac myocyte or connective tissue elements. Our results suggest that the growth of myocardial fibres and the increase in volume of interstitial elements in the hypertrophic heart are under independent genetic control.
DIFFERENTIAL EFFICACY OF PERINDOPRIL AND ENALAPRIL IN EXPERIMENTAL DIABETIC NEPHROPATHY
Authors: Duggan KA , Hodge G. , Makarious MM , Charlesworth JA
Published: June 2007

1. Treatment with angiotensin converting enzyme (ACE) inhibitors ameliorates human and experimental diabetic nephropathy, possibly as a result of changes in angiotensin II (AngII) and/or bradykinin concentrations. However, ACE is an indiscriminate enzyme, which hydrolyses numerous vasoactive peptides at two catalytic sites that are thought to be substrate specific. AngI is cleaved at the C‐terminal site, bradykinin at both the C‐ and N‐terminal sites, while other substrates may be preferentially cleaved at the N‐terminal site. Of the various ACE inhibitors, some (e.g. perindopril) bind preferentially to the C‐terminal site while others (e.g. enalapril) bind to both. We compared the efficacy of perindopril and enalapril in the diabetic SHR to determine whether all the benefits of ACE inhibition derive from changes in the concentrations of C‐terminal related substrates.

2. Diabetes was induced by tail vein injection of streptozotocin (60 mg/kg) in 14 week old SHR. Blood glucose was maintained at 4–8 mmol/L by daily ultralente insulin injection and rats were randomized to control, enalapril (10 mg/kg per day) or perindopril (4 mg/kg per day) groups. Blood pressure, creatinine clearance and urinary protein excretion were monitored for 3 months.

3. Blood pressure in both treatment groups was lower than in control (perindopril P<0.0001; enalapril P<0.0001). Levels were marginally higher in the perindopril group than the enalapril group, although this difference was significant only in the second month (P<0.025). Creatinine clearance was significantly lower in the perindopril group (0.44 ± 0.05 mL/min) than in either the control rats (0.85 ± 0.11 mL/min; P<0.001) or the enalapril‐treated group (0.66 ± 0.05 mL/min; P<0.005). Proteinuria was also lower in this group (4.3 ± 0.9 mg/24h) than in the enalapril‐treated (11.3 ± 5.8 mg/24h; P<0.05) or control groups (32.1 ± 4.5 mg/24h; P<0.0005).

4. The difference in efficacy between perindopril and enalapril that we have observed suggests that the benefits of ACE inhibition derive from changes in the concentrations of peptides catalysed by the C‐terminal rather than the N‐terminal site.
LOW AFFINITY NERVE GROWTH FACTOR RECEPTOR GENE CO‐SEGREGATES WITH DECREASED BODYWEIGHT AND INCREASED LEFT VENTRICULAR WEIGHT IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kapuscinski MK , Nemoto K. , Ueyama T. , Charchar F. , Kageyama H. , Fukumachi K. , Sekimoto M. , Senba E. , Tomita T. , Tomita I. , Harrap SB
Published: June 2007

1. The sympathetic nervous system influences the cardiovascular and hormonal systems and sympathetic innervation is dependent on nerve growth factor (NGF). The NGF gene is linked genetically to high blood pressure in the spontaneously hypertensive rat (SHR) and there exists a mutation in the SHR low affinity NGF receptor (LNGFR) gene.

2. To determine whether the LNGFR mutation was linked genetically with cardiovascular phenotypes we studied an F2 population derived from SHR and normotensive Donryu (DRY) rats.

3. Mean arterial pressure (MAP), left ventricular mass (LVM) and related phenotypes were measured in 127 20 week old male F2 rats and correlated with the inheritance of the SHR mutation (S) and/or the DRY allele (D) of the LNGFR.

4. Analysis of variance revealed that the S mutation was associated with a significantly lower bodyweight in F2 rats (P<0.0001).

5. The S mutation was associated with a significant (P<0.007) increase in LVM: bodyweight ratio, but not with differences in right ventricular or kidney weights corrected for bodyweight. We found no association between MAP and LNGFR alleles or genotypes.

6. These results suggest that the mutation in the signal peptide of LNGFR may serve as a useful marker for the analysis of genetic factor(s) involved in the differential determination of body size and heart weight.