bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPARATIVE RELAXANT EFFECTS OF CROMAKALIM AND PINACIDIL ON THE TONIC CONTRACTION OF CANINE CORONARY ARTERY INDUCED BY PHORBOL 12,13‐DIBUTYLATE
Authors: Kuromaru O. , Sakai K.
Published: June 2007

1. Phorbol esters, activators of protein kinase C (PKC), have been widely used to investigate the role of PKC in the regulation of smooth muscle contraction. However, limited studies have so far been made of the sensitivity of the contraction induced by phorbol esters to relaxant drugs. We therefore examined the relaxant effects of the K+ channel openers, cromakalim and pinacidil, on the tonic contraction of canine isolated coronary artery rings induced by phorbol 12,13‐dibutylate (PDBu).

2. In rings contracted with 10−7mol/L PDBu, cromakalim and pinacidil, as well as nifedipine, produced a concentration‐dependent relaxation. At their maximum effects, both cromakalim and nifedipine caused a partial relaxation, whereas pinacidil produced nearly a full relaxation.

3. The relaxant effects of cromakalim and pinacidil were effectively antagonized by the ATP‐sensitive K+ channel blocker, glibenclamide (10−6mol/L).

4. In the presence of nifedipine, high K+ was ineffective while PDBu (10−7mol/L) still induced a tonic contraction. This PDBu‐induced contraction was inhibited by concentrations of cromakalim and pinacidil higher than those needed in the absence of nifedipine.

5. In rings partially depolarized with 35mmol/L KCl, the ability of cromakalim to inhibit PDBu‐induced contractions in the presence of nifedipine was completely abolished. Under the same conditions, the relaxant response to pinacidil, unlike cromakalim, was inhibited only partially.

6. These results suggest that cromakalim inhibits PDBu‐induced contractions through an opening of K+ channels. Pinacidil does so by a mechanism shared with cromakalim as well as by another that is independent of this K+ channel opening action. These multiple modes of action may confer on pinacidil a vasorelaxant activity greater than that of cromakalim.
DIETARY FISH OIL PREVENTS THE DEVELOPMENT OF RENAL DAMAGE IN SALT‐LOADED STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Hobbs Leanne M , Rayner Timothy E , Howe Peter RC
Published: June 2007

1. Stroke‐prone spontaneously hypertensive rats (SHRSP) fed a high salt diet rapidly develop proteinuria, a marker of renal damage. We have recently shown that supplementing the diet of these rats with pure omega‐3 fatty acids can inhibit the development of proteinuria. The aim of the present study was to examine the underlying renal pathology and to see whether a similar benefit could be obtained with fish oil or canola oil.

2. Diets containing sodium (2% by weight) and 5% fish oil, canola oil, olive oil or safflower oil (the latter two serving as controls) were fed to groups of eight young SHRSP and the development of hypertension and proteinuria was monitored. After 9 weeks, rats were killed and their kidneys were taken for histological examination and fatty acid analysis. Urinary protein was characterized electrophoretically.

3. Patterns of protein excretion were consistent with the appearance of pathological changes in both glomeruli and tubules. Fish oil inhibited the elevation of blood pressure, prevented the development of proteinuria and minimized histological lesions. However, in rats fed canola oil, hypertension and renal damage were equally severe as in rats fed olive or safflower oil.

4. The prevention of hypertensive renal damage by dietary fish oil may be attributable to increased incorporation of longchain omega‐3 fatty acids in the kidney.
EFFECT OF COFFEE AND TEA DRINKING ON POSTPRANDIAL HYPOTENSION IN OLDER MEN AND WOMEN
Authors: Rakic V. , Beilin LJ , Burke V.
Published: June 2007

1. A postprandial fall in blood pressure (BP) in older men and women increases the risks of falls and impaired cerebral perfusion. Postprandial hypotension has been suggested to be greater in hypertensive subjects, particularly in those on antihypertensive medication.

2. Caffeine, given as tablets or as strong coffee, may attenuate postprandial falls in BP in older subjects, but findings are not consistent.

3. In a randomized controlled intervention in 171 healthy non‐smokers over the age of 50 years, we compared the effects of coffee‐drinking with abstaining from caffeine in normotensives (NT), untreated hypertensives (UNHT) and subjects on drug treatment for hypertension (TRHT). Tea drinking was a third intervention used only in TRHT.

4. After adjustment for the effects of the initial value on changes in BP, there were no significant differences related to hypertension or to antihypertensive agents in the magnitude of postprandial falls in BP.

5. After the intervention, changes in fasting supine and standing systolic BP and heart rate (HR) were not significantly different from controls in NT, UNHT and TRHT, but fasting supine and standing diastolic BP were significantly higher in coffee drinkers in the UNHT group.

6. In normotensive coffee drinkers there was a significant reduction in the postprandial fall in supine systolic BP of 4.1 mmHg (± s.e.m. 1.1) and in standing systolic BP of 5.2 ± 1.6 mmHg. Among untreated hypertensives, abstainers showed a significant attenuation of the postprandial fall in supine, but not standing, systolic BP. Among treated hypertensives who were tea drinkers the postprandial fall decreased for supine systolic BP by 3.8 ± 1.2 mmHg (P= 0.029) and for standing systolic BP by 5.2 ± 2.1 mmHg.

7. Both tea and coffee were potentially beneficial in decreasing postprandial falls in systolic BP, but coffee drinking may increase fasting diastolic pressures in untreated hypertensives.
VALIDATION OF AN ECHOCARDIOGRAPHIC ASSESSMENT OF CARDIAC FUNCTION FOLLOWING MODERATE SIZE MYOCARDIAL INFARCTION IN THE RAT
Authors: Burrell Louise M , Chan Robert , Phillips Paddy A , Calafiore Paul , Tonkin Andrew M , Johnston Colin I
Published: June 2007

1. The present study determined whether two dimensional guided M‐mode echocardiography could assess left ventricular (LV) geometry and function following a moderate size myocardial infarction in the rat.

2. Myocardial infarction (MI) was induced by left coronary artery ligation and rats were studied 4 weeks later. Infarct rats showed increased LV internal diastolic diameter (7.33 ± 0.8 vs 5.91 ± 0.6 mm; P > 0.001), LV systolic diameter (3.73 ± 1.2 vs 1.87 ± 0.6 mm; P > 0.001) and thickening of the noninfarcted posterior wall compared with sham operated rats (1.81 ± 0.2 vs 1.47 ± 0.3; P > 0.001; n= 10/group; mean ± s.d.). Systolic function was impaired in infarct rats who showed reduced fractional shortening (50 ± 12 vs 68 ± 9%; P > 0.001) and fractional area change (41 ± 14 vs 78 ± 5%; P > 0.001). Infarct size measured echocardiographically was comparable to that measured by quantitative histological examination (29 ± 10 vs 28 ± 5%; NS).

3. The present study indicates that postinfarction remodelling leading to LV cavity dilation, hypertrophy of surviving myocardium and impaired systolic function is apparent 4 weeks following moderate size MI in the rat.

4. Transthoracic echocardiography is a noninvasive technique that may be used to assess serially the efficacy of therapeutic interventions designed to prevent remodelling in moderate size MI in the rat.
REGULATION BY PROTEIN KINASE C OF TRANSFORMING GROWTH FACTOR‐β1 ACTION ON THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS FROM SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Saltis John , Bobik Alex
Published: June 2007

1. This study examined the role of protein kinase C (PKC) on the action of transforming growth factor‐β1 (TGF‐β1) to regulate the proliferation of vascular smooth muscle cells (VSMC) isolated from the aorta of the spontaneously hypertensive rat (SHR).

2. Down‐regulation of PKC by prolonged exposure to phorbol 12‐myristate 13‐acetate (PMA) completely inhibited the ability of TGF‐β1 to potentiate epidermal growth factor‐stimulated proliferation of VSMC.

3. In contrast, the inhibitory effect of TGF‐β1 on serumstimulated proliferation of VSMC was not altered by PMA action.

4. These results suggest that PKC‐dependent signalling pathways involved in the regulation of growth by TGF‐β1 may be important in any proliferative component of vascular hypertrophy that develops in the SHR.
NEW DIAGNOSTIC TESTS FOR CUSHING'S SYNDROME: USES OF NALOXONE, VASOPRESSIN AND ALPRAZOLAM
Authors: Jackson RV , Hockings GI , Torpy DJ , Grice JE , Crosbie GV , Walters MM , Strakosch CR
Published: June 2007

1. We set out to investigate whether the administration of naloxone alone, naloxone plus vasopressin (AVP) or naloxone plus alprazolam to patients with Cushing's syndrome would result in a blunted dynamic response of the pituitary‐adrenal axis compared with normal volunteers. Cushing's syndrome is often difficult to diagnose. It would be helpful if new tests were available to help in the biochemical distinction between Cushing's syndrome and non‐Cushing's syndrome patients.

2. Naloxone testing correctly distinguished all seven patients with Cushing's syndrome (four pituitary Cushing's, two adrenal adenomas, one ectopic ACTH) from normal. Six patients were distinguished by the per cent change of plasma ACTH from basal being less than the normal range of 10 volunteers. The seventh patient (a pituitary Cushing's) was distinguished by the per cent change from basal of plasma cortisol being less than the normal range.

3. Naloxone plus AVP testing of two of four patients with pituitary Cushing's showed a smaller per cent change for both ACTH and cortisol compared with five normal volunteers, correctly distinguishing Cushing's from the normals.

4. Naloxone plus alprazolam did not distinguish Cushing's from normal.

5. Naloxone testing and naloxone plus AVP testing appear to be promising methods of distinguishing Cushing's syndrome from normal. Further experience with these tests, especially with obese and pseudo‐Cushing's individuals, will be necessary to determine their place in the diagnosis and differential diagnosis of the cause of Cushing's syndrome.
DIFFERENT ALLELIC PATTERNS AT CHROMOSOME 11q13 IN PAIRED ALDOSTERONE‐PRODUCING TUMOURS AND BLOOD DNA
Authors: Gordon Richard , Gartside Michael , Tunny Terry , Stowasser Michael
Published: June 2007

1. We previously reported loss of heterozygosity (LOH) at region q13 of chromosome 11 in five aldosterone‐producing tumours (APT) using restriction fragment length polymorphism (RFLP) analysis, including two from patients with familial hyperaldosteronism.

2. In the present study, microsatellite markers were used to examine 33 informative paired blood and tumour DNA samples from patients with APT for LOH at three loci that map to chromosome 11q13.

3. LOH at one or more loci was detected in seven (21.2%) tumour DNA samples.

4. This study provides further support that mutations at 11q13 may be involved in the underlying pathophysiology of aldosterone‐producing tumours of the adrenal cortex.
CARDIAC GROWTH DURING HIGH AND LOW DOSE PERINDOPRIL TREATMENT IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Black MJ , Bertram JF , Johnston CI
Published: June 2007

1. The effect of high and low dose angiotensin converting enzyme (ACE) inhibition and the contribution of bradykinin potentiation in this treatment on left and right ventricle weights and wall volume was investigated in immature spontaneously hypertensive rats (SHR).

2. Male SHR were treated from 7 to 11 weeks of age with perindopril (an ACE inhibitor) at a low dose of 0.1 mg/kg per day or a high dose of 1 mg/kg per day. Half the animals were also treated with a bradykinin receptor antagonist, HOE 140 (500 μg/kg per day).

3. After 4 weeks of treatment, hearts were arrested in diastole and perfusion fixed. The right and left ventricle plus septum were weighed, cut into 1 mm slices and volume was determined using the Cavalieri principle.

4. Low dose perindopril treatment did not significantly affect blood pressure in the SHR. High dose perindopril treatment maintained blood pressure at a level similar to Wistar‐Kyoto (WKY) rats.

5. Growth of the right ventricle was not influenced by ACE inhibition. However, high dose treatment significantly lowered the left ventricle plus septum volume: bodyweight ratio (LV + S VOL:BWT) compared with control SHR (2.85 ± 0.02 vs 3.36 ± 0.08 mm3/g, respectively) to a level similar to the normotensive WKY rats (2.80 ± 0.11 mm3/g). Similarly, low dose treatment significantly lowered the LV + S VOL:BWT ratio (2.89 ± 0.09 mm3/g). HOE 140 treatment did not reverse the effect of ACE inhibition. Similar effects were observed on left ventricular weights.

6. ACE inhibition, independent of its blood pressure lowering effect, prevents the development of left ventricular hypertrophy in the SHR but does not influence growth of the right ventricle. This effect of ACE inhibition does not appear to be mediated by bradykinin potentiation.
CHANGES IN ANGIOTENSIN II METABOLISM CONTRIBUTE TO THE INCREASED PRESSOR RESPONSE TO ANGIOTENSIN AFTER CHRONIC TREATMENT WITH l‐NAME IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Yang Y. , Macdonald GJ , Duggan KA
Published: June 2007

1. Administration of nitric oxide (NO) synthase inhibitors, such as l‐NAME, is associated with an increase in blood pressure and an increase in pressor responsiveness to infused angiotensin II (AngII). The present study was designed to investigate the contribution of changes in the metabolism of AngII to the enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR; 14 weeks old) chronically treated with l‐NAME.

2. Group I rats received l‐NAME for 7 days (5 mg/kg per day) in their drinking water. Group II rats received water only. On day 7, rats were anaesthetized and metabolic clearance studies were performed. AngII concentrations in plasma and infusate were measured by radioimmunoassay.

3. Urinary NO2 was unchanged after l‐NAME treatment, while NO3 decreased compared with control. Mean arterial pressure (MAP) was higher in the l‐NAME treated rats than in control. After 30min infusion of AngII, MAP increased significantly in both groups, although the increase was larger in l‐NAME‐treated than control rats. The metabolic clearance rate of AngII was significantly lower in l‐NAME‐treated rats than in the control group.

4. We conclude that chronic NO synthase inhibitors, such as l‐NAME, cause a decrease in the rate at which AngII is metabolized. This decrease, in combination with the increase in the number of vascular AngII receptors, may account for the reported increase in pressor responsiveness to infused AngII.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ANGIOTENSIN RECEPTORS AND DEVELOPMENT: THE KIDNEY
Authors: Alcorn Daine , McCausland Jane E , Maric Christine
Published: June 2007

This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development.

Several components of the renin‐angiotensin system (RAS) are detected in the foetal kidney early in development.

Angiotensin II is essential for normal foetal and neonatal renal function.

Angiotensin II receptors transduce important signals leading to growth and development.

Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development.

Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT1 subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations.

While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth.

In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade.

In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculature.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN
Authors: McKinley MJ , McAllen RM , Pennington GL , Smardencas A. , Weisinger RS , Oldfield BJ
Published: June 2007

Autoradiographic binding studies have shown that the AT1 receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT1 receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco‐lumbar spinal cord.

While there are differences between species, AT2 receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.

Circulating AngII acts on AT1 receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.

Centrally administered AngII may act on AT1 receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.

Recent evidence shows that centrally administered AT1 antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.

Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT1 receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA
Authors: Dampney RAL , Hirooka Y. , Potts PD , Head GA
Published: June 2007

It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.

The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non‐cardiovascular neurons in this region.

It is known that pressor neurons in the rostral VLM include both catecholamine and non‐catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.

It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.
ANTEROVENTRAL WALL OF THE THIRD VENTRICLE AND DORSAL LAMINA TERMINALIS: HEADQUARTERS FOR CONTROL OF BODY FLUID HOMEOSTASIS?
Authors: McKinley MJ , Pennington GL , Oldfield BJ
Published: June 2007

1. The subfornical organ, median preoptic nucleus and the organum vasculosum of the lamina terminalis (OVLT) are a series of structures situated in the anterior wall of the third ventricle and form the lamina terminalis. The OVLT and ventral part of the median preoptic nucleus are part of a region known as the anteroventral third ventricle region.

2. Data from many laboratories, using techniques ranging from lesions, electrophysiology, neuropharmacology, Fos expression, immunohistochemistry and receptor localization, indicate that the tissue in the lamina terminalis plays a major role in many aspects of body fluid and electrolyte balance.

3. The subfornical organ and OVLT lack the blood‐brain barrier and detect alterations in plasma tonicity and the concentrations of circulating hormones such as angiotensin II and possibly atrial natriuretic peptide and relaxin.

4. This information is then integrated within the lamina terminalis (probably in the median preoptic nucleus) with neural signals from other brain regions. The neural output from the lamina terminalis is distributed to a number of effector sites including the paraventricular (both parvo‐ and magno‐cellular parts) and supraoptic nuclei and influences vasopressin secretion, water drinking, salt intake, renin secretion, renal sodium excretion and cardiovascular regulation.
RELATIVE CONTRIBUTIONS OF EXTRACELLULAR Ca2+ AND Ca2+ STORES TO SMOOTH MUSCLE CONTRACTION IN ARTERIES AND ARTERIOLES OF RAT, GUINEA‐PIG DOG AND RABBIT
Authors: Low AM , Kotecha N. , Neild TO , Kwan CY , Daniel EE
Published: June 2007

1. These studies describe the functional effects of modulation of the sarcoplasmic reticulum (SR) Ca2+ stores at three levels of the vasculature: (i) large arteries (rat and guinea‐pig aorta); (ii) small resistance arteries (rat tail artery, rabbit mesenteric artery, dog mesenteric artery); and (iii) arterioles (guinea‐pig submucosal arterioles of the small intestine).

2. All tissues responded to phenylephrine (PE; 10 μmol/L) with a transient contraction in Ca2+‐free Krebs', reflecting Ca2+ release from PE‐sensitive Ca2+ stores. After pretreatment with cyclopiazonic acid (CPA; 30 μmol/L) or thapsigargin (TSG; 1 μmol/L), putative SR Ca2+ pump inhibitors, the PE‐induced contraction in a Ca2+‐free medium was significantly inhibited in arterial tissues at all levels of the vasculature. Similarly, ryanodine (RYA; 30 μmol/L), an agonist that enhances Ca2+ release from the SR, also reduced the PE contraction in a Ca2+‐free solution.

3. CPA or TSG alone in the presence of extracellular Ca2+, caused marked and sustained contraction in the rat and guinea‐pig aorta and marked but transient or no contraction in the resistance arteries. In the rat and guinea‐pig aorta, RYA caused a slowly developing tension. Little increase in basal tension was produced by RYA in resistance arteries and arterioles.

4. The findings show that an agonist‐releasable Ca2+ pool is present at all levels of the vasculature that is independent of the size of the vessels and suggest that under normal physiological conditions there is an intimate balance between the roles of the plasma membrane and of the SR in the maintenance of vascular contractility. It appears that the role of the SR diminishes as the arteries become smaller, while Ca2+ fluxes across the plasma membrane predominates.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELIN RECEPTORS IN NORMAL AND DISEASED KIDNEYS
Authors: Nambi Ponnal
Published: June 2007

1. Endothelin‐1 (ET‐1), the most potent vasoconstrictor yet identified, mediates a multitude of responses in various tissues including the kidney. The biological responses of ET‐1 are mediated by specific cell surface receptors classified as ETA and ETB. Species differences are observed in the distribution as well as function of these ET receptors.

2. Involvement of ET has been demonstrated in a number of renal diseases, including ischaemia‐induced acute renal failure, chronic renal failure, radiocontrast and cyclosporin‐induced nephrotoxicity. ET antibodies as well as ET receptor antagonists have been shown to be beneficial in these disease models.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELIN IS A KEY MODULATOR OF PROGRESSIVE RENAL INJURY: EXPERIMENTAL DATA AND NOVEL THERAPEUTIC STRATEGIES
Authors: Bruzzi Isabella , Benigni Ariela
Published: June 2007

1. Glomerulosclerosis and tubulointerstitial damage are common histological abnormalities of many renal diseases that progress to end‐stage renal failure.

2. In some models of renal damage, glomerulosclerosis seems to be associated with increased glomerular capillary pressure.

3. Due to the positive correlation of glomerulosclerosis and proteinuria in both experimental models and in humans, abnormal permeability to macromolecules has also been considered a possible determinant of glomerulosclerosis.

4. Abnormally filtered macromolecules have an intrinsic toxicity to the kidney due to protein over‐reabsorption, possibly leading to tubulointerstitial damage.

5. Endothelin‐1 (ET‐1) is a vasoconstrictor peptide that induces mitogenesis and the accumulation of matrix proteins by mesangial cells.

6. Evidence is available that ET‐1 plays a role in progressive renal disease in different experimental models, including renal mass reduction, lupus nephritis, streptozotocin‐induced diabetes and puromycin‐induced nephrosis.
NEW INSIGHTS INTO VASCULAR REACTIVITY: FROM ALTERED STRUCTURE TO NEURAL CONTROL*
Authors: Angus James A.
Published: June 2007

1. The present review covers two aspects of the author's research into the pharmacology of vascular reactivity of isolated vessels and in the intact circulation. First, how ‘normal’ reactivity is altered by injury or disease and, second, how novel drugs have allowed insight into the role of the cotransmitter neuropeptide Y and ‘N’ type calcium channels in neurotransmitter release.

2. Acute endothelium removal in the femoral artery of the anaesthetized dog confirmed the obligatory role of these cells in the dilatation response to intra‐arterial acetylcholine (ACh). After 4 weeks, conduit arteries respond with a thickened neoin‐tima following acute endothelial injury but, provided macrophage‐derived foam cells are absent, the artery relaxes normally to ACh.

3. In the dog coronary vasculature, stable collateral arteries have a marked neointima of non‐contractile smooth muscle cells that are lined with endothelium. Reactivity to vasodilator stimuli is normal while that to vasoconstrictor stimuli is impaired.

4. In the conscious rabbit, superficial femoral artery (SFA) occlusion stimulates profound angiogenesis but, despite these changes to the hindlimb vasculature, reactivity to vasodilator and vasoconstrictor agents from day 1 to 6 months following SFA is unaltered.

5. Endothelial dysfunction is discussed in relation to hypertension, hypercholesterolaemia and congestive heart failure.

6. The novel ‘N’ type calcium channel antagonist co‐conotoxin GVIA, was used to explore the role of ‘N’ type channels in cardiac and vascular neurotransmitter release in conscious rabbits.

7. The novel putative Yi‐selective neuropeptide Y antagonist 1229U91 was shown to inhibit nerve‐mediated contractions of isolated mesenteric, but not femoral, artery segments in the rat. This regional difference in a possible cotransmitter role of the peptide is discussed.
EFFECT OF GENOTYPE ON THE ANGIOTENSIN‐CONVERTING ENZYME mRNA LEVEL IN HUMAN ATRIA
Authors: Tamaki Shinji , Iwai Naoharu , Ohmichi Nobuyuki , Shimoike Hitoshi , Izumi Masafumi , Nakamura Yasuyuki , Kinoshita Masahiko , Katsuyama Kazuhiko , Sugita Takaaki , Watarida Shouji , Mori Atsumi
Published: June 2007

1. To clarify the mechanism of the association between I/D polymorphism of the angiotensin‐converting enzyme (ACE) gene and various cardiovascular diseases, ACE mRNA levels in human atrial appendages were assessed in relation to the genotype of the ACE gene.

2. Angiotensin‐converting enzyme mRNA levels were positively correlated with age and tended to show a positive correlation with mean pulmonary pressure (niPA). Multiple regression analysis indicated that age and mPA, but not the genotype of the ACE gene, were predictors of ACE mRNA levels in human atrial appendages.

3. The present study indicates that I/D polymorphism of the ACE gene is not simply reflected in ACE mRNA levels and that further study is needed to determine the mechanism of the association between this polymorphism and various cardiovascular diseases.
IMPROVING EFFECT OF CARTEOLOL ON BODYWEIGHT AND CARBOHYDRATE AND LIPID METABOLIC RESPONSES IN THE OLETF RAT
Authors: Saitoh Yuichi , Tani Takeshi , Asahi Yoshihiko , Man Zhiwei , Kawano Kazuya , Ikunaga Hideyuki
Published: June 2007

1. Carteolol, a non‐selective beta‐blocker with intrinsic sympathomimetic activity, admixed in a pellet diet was administered to Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous non‐insulin‐dependent diabetes mellitus with mild obesity. A high dose of carteolol (0.02%) suppressed bodyweight gain without affecting food and water consumption until the appearance of glycosuria. Carteolol tended to reduce the cumulative incidence of glycosuria at 26 weeks after the beginning of administration (55,17 and 25% in control rats, and in rats fed a low (0.002 %) and high dose of carteolol, respectively).

2. At the 26th week of administration, the high dose of carteolol decreased visceral fat weight, such as that of retroperitoneal and epididymal adipose tissue, whereas the liver and the kidney were not affected.

3. Although plasma glucose and triglyceride levels in non‐fasted rats were elevated with age, carteolol tended to delay the increases in those parameters. Carteolol suppressed the increase in plasma glucose levels, which indicate the diabetic pattern, in a 25th week oral glucose tolerance test.

4. These findings indicate that carteolol induces improvements in bodyweight and carbohydrate and lipid metabolism in an obese condition. Consequently, carteolol may be useful for the treatment of hypertension with obesity in order to prevent cardiovascular events.
NITRIC OXIDE DEFICIENCY INDUCES MYOCARDIAL INFARCTION IN HYPERCHOLESTEROLAEMIC STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ikeda Katsumi , Nara Yasuo , Tagami Motoki , Yamori Yukio
Published: June 2007

1. To observe the effect of nitric oxide (NO) on the myocardium, the NO synthesis inhibitor NG‐nitro‐L‐arginine (L‐NNA) was administered to hypercholesterolaemic stroke‐prone spontaneously hypertensive (SHRSP) rats.

2. Hypercholesterolaemic SHRSP were produced by feeding SHRSP a high fat and high cholesterol diet (HFC) for 2 weeks. The rats were then divided into three groups: (i) the N group, which were fed the HFC diet containing 0.023% L‐NNA and 1% NaCl in their drinking water (n = 10); (ii) the NH group, which were fed the HFC diet containing 0.023% L‐NNA and 1% NaCl in their drinking water which also contained 80 mg/L hydralazine (n = 10); and (iii) the C group, which were fed the HFC diet and 1% NaCl in their drinking water (n = 10).

3. All rats in the N and NH groups died within 35 days of the initiation of L‐NNA administration. Rats in the N and NH groups had significantly increased serum creatine phosphokinase, lactate dehydrogenase, glutamic oxaloacetic transaminase and serum total cholesterol levels compared with rats in the C group.

4. Fibrosis in response to necrosis was histopathologically observed in the hearts of all rats in the N and NH groups without exception. Occlusion or intimal thickening in the arteries adjacent to the necrotic regions was also observed.

5. These results suggest that nitric oxide deficiency induces myocardial infarction in hypercholesterolaemic SHRSP. These NO‐deficient hypercholesterolaemic SHRSP offer a new model of myocardial infarction in rats.
RENAL REGULATION OF PHOSPHATE EXCRETION IN ENDOTOXAEMIC RATS
Authors: Mimura Yoshikazu , Uno Keizo , Nakamura Takuro
Published: June 2007

1. Maintenance of phosphate homeostasis is essential for energy producing and oxygen delivery systems, particularly, when the energy requirements are increased in certain conditions, such as septicaemia. We investigated the phosphaturic response to parathyroid hormone (PTH) in endotoxin (ETx)‐treated rats in order to clarify the renal regulation of phosphate excretion during endotoxaemia.

2. Wistar rats that had undergone thyroparathyroidectomy were challenged with either Escherichia coli ETx (n= 8) or saline vehicle (n = 9). Thirty‐minute renal clearance tests were done before and after PTH infusion. Rats infused with saline instead of PTH served as time controls for the ETx‐ (n= 7) and saline‐treated (n = 8) rats.

3. In time control rats, ETx administration enhanced phosphate excretion progressively and this was associated with an obvious increase in the level of kidney adenosine 3′,5′‐cyclic mono‐phosphate (P < 0.005) compared with levels following saline vehicle administration. However, this phosphaturia in late‐phase endotoxaemia was not observed in rats infused with PTH; ETx, but not saline vehicle, blunted the PTH‐mediated increase in phosphate excretion (P < 0.005). Increased urinary noradrenaline, and constant dopamine excretion were observed in endo‐toxaemic rats. Endotoxin administration produced marked metabolic acidosis and hypocapnia in comparison with the administration of the saline vehicle.

4. To test whether renal tubular sensitivity to parathyroid hormone related‐protein (PTHrP) was enhanced during endotoxaemia, phosphaturic response to PTHrP in ETx‐ (n = 7) and saline‐treated rats (n= 7) was examined. Parathyroid hormone related‐protein infusion produced phosphaturia in both groups. However, the severity of the phosphaturia after PTHrP infusion was less in ETx‐ than in saline‐treated rats.

5. In summary, although ETx administration causes a progressive increase in phosphate excretion in the absence of PTH, this is overcome by the antiphosphaturic effect of ETx, attenuating PTH‐mediated phosphaturia after PTH infusion.
FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY
Authors: Reid CM , Nelson M. , Beckinsale P. , Ryan P. , Wing LMH , Beilin LJ , Brown MA , Jennings GLR , Johnston CI , Marley J. , McNeil JJ , Morgan TO , Shaw J. , Steven ID , West MJ
Published: June 2007

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices.

2. General practitioners (GPs) were invited to participate by mail and personal follow‐up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg.

3. Seven hundred and forty‐one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty‐two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty‐seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty‐seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population).

4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.
ENDOTOXIN ALTERS THE SYSTEMIC DISPOSITION OF NITRIC OXIDE SYNTHASE INHIBITORS IN THE AWAKE SHEEP
Authors: Rutten AJ , Bersten AD , Whiting MJ
Published: June 2007

1. We evaluated the haemodynamic effects and systemic disposition of the nitric oxide synthase (NOS) inhibitor NL‐nitro‐L‐arginine (NOLA) after intravenous (i.v.) administration of two different doses (5 and 20 mg/kg) in awake healthy sheep and awake sheep given a continuous i.v. infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i.v., for 18 h). In addition, we determined the systemic disposition of another NOS inhibitor, NL‐nitro‐L‐arginine methylester (L‐NAME; 20 mg/kg, i.v.) in awake healthy sheep only.

2. ArL‐Nitro‐L‐arginine produced a dose‐dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose‐dependent increase in mean arterial pressure (MAP) and peripheral vascular resistance (PVR) when compared to baseline. In endotoxic sheep NOLA produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP).

3. In healthy sheep there was a dose‐related increase in total body clearance (CI) of NOLA. The CI increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose. The infusion of endotoxin caused an increase in CI of NOLA to 0.040 and 0.047 L/min, respectively, and a decrease in plasma slow half‐life (t1/2 from 825 to 546 min and from 780 to 453 min, respectively.

4. NL‐Nitro‐L‐arginine methylester was rapidly cleared from the plasma with a slow half‐life of approximately 7.5 min and there was a simultaneous appearance of NOLA in the plasma.

5. These results support the view that nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in CI of NOLA with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical studies.
SKELETAL MUSCLE RESTING METABOLISM IN COLD‐ACCLIMATED RATS: EFFECT OF AGE, NORADRENALINE AND HYPEROSMOLARITY
Authors: Cox Jason P. , Gibbs Colin L.
Published: June 2007

1. A myothermic technique has been used to measure the resting metabolism of small bundles of a fast twitch muscle, extensor digitorum longus (EDL), and a slow twitch muscle, soleus (SOL), in 7‐week‐old rats. At 27°C, mean (± SEM) resting heat rates were 2.33 ± 0.41 and 2.09 ± 0.37 mW/g in EDL and SOL, respectively (n= 16).

2. Seven‐week‐old rats were cold acclimatized at 4°C for 1–4 weeks and the metabolic rates of the fast and slow twitch muscles were monitored and compared with 7‐ and 11‐week‐old controls. There was a 160% increase in metabolic rate from week 7 to week 11, but the increase also occurred in the control group.

3. In accordance with several literature reports, noradrenaline at concentrations of 10”7 and 10”6 mol/L had no effect on either the control or cold‐acclimatized resting heat rate.

4. The osmolarity of the physiological solution bathing the muscle bundles was increased by lOOmosmol using sodium sulphate. Basal metabolism increased by similar amounts (approximately 250%) in both the fast and slow muscle bundles. Periods of cold exposure had no significant effect on the magnitude of the increment.

5. Bumetanide, a potent inhibitor of Na+‐Cl− co‐transport, produced only a slight reduction in the heat increments caused by hyperosmolar challenge.
ALTERATIONS OF mRNA LEVELS OF ai‐ADRENOCEPTOR SUBTYPES WITH MATURATION AND AGEING IN DIFFERENT RAT BLOOD VESSELS
Authors: Xu Kai‐ming , Tang Fai , Han Chide
Published: June 2007

1. Alterations of mRNA levels of ai‐adrenoceptor subtypes during maturation and ageing were determined by reverse trans‐cription‐polymerase chain reaction (RT‐PCR) in aortae and renal, pulmonary and mesenteric arteries isolated from 3,12 and 24‐month‐old rats.

2. The steady state levels for α1A‐, α1B‐ and α1D‐adrenoceptors in aorta declined with maturation and ageing. In renal artery there was a decrease in mRNA for the α1B‐adrenoceptor in aged rats. However, in mesenteric and pulmonary arteries there were no changes in mRNA levels for the three subtypes of α1‐adrenoceptors as a result of maturation and ageing.

3. The results suggest that expression of α1‐adrenoceptors is changed heterogeneously in different blood vessels during maturation and ageing in rats.
A NITRIC OXIDE DONOR (SPERMINE‐NONOATE) PREVENTS THE FORMATION OF NEOINTIMA IN RABBIT CAROTID ARTERY
Authors: Yin ZL , Dusting GJ
Published: June 2007

1. In the present study we investigated the effect of spermine diazeniumdiolate (spermine‐NONOate), a nitric oxide donor, on the early development of atheroma‐like lesions induced by a peri‐arterial collar in rabbits.

2. Spermine‐NONOate was given locally by incorporating the compound (1 mg/mL) into a silastic collar, which was applied on one common carotid artery of rabbit while the other carotid artery had a placebo collar (without compound) applied.

3. Fourteen days postimplantation, both carotid arteries were dissected free for histological study (n = 6).

4. After 14 days with collars, treatment with spermine‐NONOate had significantly reduced (by 74%) the thickness of the neointima in comparison with the contralateral collared artery without compound. Blood pressure did not change during treatment. Nitric oxide, detected as nitrite, was still released from spermine‐NONOate silastic collars after 14 days implantation.

5. These results suggest that locally administered spermine‐NONOate is effective in slowing the development of neointima in this model.
CHRONIC INTRARENAL INFUSION OF LOW‐DOSE ANGIOTENSIN II IN DOGS INCREASES ARTERIAL PRESSURE WITHOUT IMPAIRMENT OF RENAL FUNCTION
Authors: Stevenson Kathleen M. , Fitzgerald Sharyn M. , Evans Roger G. , Anderson Warwick P.
Published: June 2007

1. To determine whether chronic angiotensin II (AngII) infusion into the renal artery, at a dose which increases systemic arterial pressure, reduces glomerular filtration rate (GFR) and renal blood flow, AngII was infused at 0.5 ng/kg per min into the renal artery or intravenously in chronically instrumented dogs for 1 month.

2. Mean arterial pressure (MAP) rose significantly (P < 0.05) during the infusion of AngII into the renal artery (+7 ± 2 nunHg on days 26‐30). There were no significant changes in GFR or renal blood flow. When the same dose of AngII was infused intravenously, MAP did not change significantly (−2 ± 2mmHg) and there were no significant changes in GFR or in renal blood flow.

3. We conclude that AngII infused into the renal artery for 1 month, at a dose which was initially subpressor, causes a rise in arterial pressure that is not associated with impairment of renal function.
ASSOCIATION OF THE BRAIN NATRIURETIC PEPTIDE GENE WITH BLOOD PRESSURE AND HEART WEIGHT IN THE RAT
Authors: Zhang Li , Xu Dong , West Malcolm J. , Summers Kim M.
Published: June 2007

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important in the control of body fluid homeostasis, blood pressure (BP) regulation and vascular remodelling. The genes for these peptides may, therefore, be involved in the pathogenesis of genetic hypertension. We have previously described a quantitative trait locus (QTL) for BP in the ANP gene region on rat chromosome 5. We have now assessed the possibility that this QTL lies at the closely linked BNP locus.

2. Intra‐arterial BP and heart weight were measured in 12‐week‐old (n = 207) and 24‐week‐old (n= 88) F2 rats derived from crosses between Wistar‐Kyoto normotensive rats and spontaneously hypertensive rats. We designed polymerase chain reaction primers to amplify a microsatellite in the BNP gene from genomic DNA. Analysis of variance was used for cosegregation analysis. Linkage mapping and localization of QTL was performed using the Mapmaker computer package.

3. A significant correlation was found between genotype for the BNP gene and systolic BP (P < 0.001) in 12‐week‐old rats. The ANP gene, but not the BNP gene, was associated with systolic BP in 24 week rats. There was no segregation of heart weight with BNP genotype at 12 or 24 weeks of age. The BNP gene mapped approximately 20 cM from the ANP gene in our rat hybrids, away from the previously described QTL. There was evidence for a second BP locus near to but distinct from the BNP gene.

4. These results suggest that BP QTL are present in the natriuretic peptide gene region but that the ANP and BNP genes themselves have no major effect on BP in this cross.
CARDIAC HYPERTROPHY IN DIABETIC SPONTANEOUSLY HYPERTENSIVE RATS: ROLE OF ANGIOTENSIN II?
Authors: Black M Jane , Briscoe Todd , Bertram John F. , Jackson Bruce , Johnston Colin I.
Published: June 2007

1. In the present study the role of angiotensin II (AngII) in the development of cardiac hypertrophy in diabetes combined with hypertension was investigated.

2. Diabetes was induced in 8‐week‐old male spontaneously hypertensive rats (SHR) by intravenous injection of streptozo‐tocin (45 mg/kg body weight). Diabetic SHR were treated with the angiotensin‐converting enzyme (ACE) inhibitor ramipril at a dose of 0.4 mg/kg per day.

3. Twelve weeks following the onset of diabetes, hearts were arrested in diastole and were perfusion‐fixed. The right ventricle and left ventricle plus septum were weighed and the volume of the ventricular walls was determined using the Cavalieri principle.

4. Induction of diabetes in SHR led to a significant reduction in bodyweight compared with non‐diabetic control SHR and this was not affected by ramipril treatment The development of hypertension was not as great in diabetic SHR compared with controls, such that at 12 weeks following the onset of diabetes systolic blood pressures (SBP) averaged 191 ± 3 and 230 ± 4 mmHg in diabetic SHR and controls, respectively. Ramipril treatment significantly lowered SBP in diabetic SHR.

5. The left ventricle plus septum volume:bodyweight ratio (LV vol:BW) was significantly higher in diabetic SHR compared with controls (3.83 ± 0.19 and 3.26 ± 0.16 mm3/g, respectively). Ramipril treatment did not affect growth of the left ventricle in diabetic SHR with the LV vol:BW ratio averaging 3.95 ± 0.14 mm3/g. Similar trends on growth were observed in the right ventricle.

6. In conclusion, the development of cardiac hypertrophy in diabetic SHR appears to occur by mechanisms independent of AngII and the elevation of blood pressure.
STIMULATION OF THE GASTRIC SODIUM MONITOR REDUCES HEPATIC ANGIOTENSIN‐CONVERTING ENZYME ACTIVITY
Authors: Duggan KA , Ye VZC
Published: June 2007

1. The natriuresis engendered by stimulation of the gastric sodium monitor is mediated in part by a decrease in the circulating concentration of angiotensin II (AngII). This decrease is due to a decrease in synthesis rather than to an increase in metabolism. We investigated the role of changes in plasma and hepatic angiotensin‐converting enzyme (ACE) activity in this decrease in AngII synthesis.

2. Male Sprague‐Dawley rats were equilibrated on a low‐sodium diet for 7 days. On the day of experiment, rats were anaesthetized and received either a sodium load of 1.5 mmol/kg as 3 mol/L saline or an equivalent volume of an iso‐osmotic urea solution by direct gastric puncture. Blood was sampled and livers were harvested at 0 and 30 min after sodium or urea administration. Angiotensin‐converting enzyme was measured in serum and tissue homogen‐ates by generation of histidyl‐leucine.

3. In the liver, ACE activity decreased from control after both sodium (P < 0.005) and urea (P < 0.025) administration. The decrease was greater in the group that received saline compared with rats that received urea (P < 0.05). Serum ACE decreased in response to urea (P < 0.025) but not sodium administration.

4. We conclude that stimulation of the gastric sodium monitor results in a decrease in ACE activity in the liver. This decrease in ACE activity may be contributory to the decrease in AngII synthesis.