bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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.
INCREASES IN THE MYOCARDIAL CONCENTRATION OF VASOACTIVE INTESTINAL PEPTIDE MAY EXPLAIN THE POSITIVE INOTROPIC EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Authors: Ye VZC , Duggan KA 
Published: June 2007

SUMMARY1. In patients with congestive cardiac failure, treatment with angiotensin converting enzyme (ACE) inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations that occur. ACE has been suggested to also metabolise vasoactive intestinal peptide (VIP), which is a positive inotrope. As VIP is synthesized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP.2. Male Sprague‐Dawley rats received enalapril (2mg/kg per day) in their drinking water or no therapy for 7 days. On day 7 the rats were anaesthetized and blood was sampled. Hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay.3. Plasma and renal concentrations of VIP did not change in enalapril‐treated rats. However, the myocardial concentration of VIP increased significantly in rats receiving enalapril compared with control animals (P<0.0005).4. We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR DETERMINANTS OF PEPTIDE AND NON‐PEPTIDE BINDING TO THE AT1 RECEPTOR
Authors: Karnik Sadashiva S , Husain Ahsan , Graham Robert M 
Published: June 2007

SUMMARY

Several residues critically involved in AT1 receptor ligand‐binding and activation have now been identified based on mutational and biochemical studies.
Asp281 and Lys199 of the rat AT1 receptor ion‐pair with Arg2 and the Phe3 α‐COOH of angiotensin II (AngII), respectively, and the Asp281/Arg2 interaction is critical for full agonist activity.
Agonist activity of AngII also requires an interaction of the Phe2 side chain with His256, which is achieved by docking of the α‐COOH with Lys199. Non‐peptide agonists interact with Lys199 and His256 in a similar fashion.
The crucial acid pharmacophores of AngII and the non‐peptide antagonist, Iosartan, appear to occupy the same space within the receptor pocket. Binding of the tetrazole anion moiety of losartan involves multiple contacts, such as Lys199 and His256. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine‐aromatic interaction.
Asp1 of AngII forms an ion‐pair with His183, which stabilizes the receptor‐bound conformation of AngII but is not critical for receptor activation.
These interactions and the involvement of other residues in stabilizing the wild‐type receptor conformation or in receptor/G‐protein coupling are considered here.
Despite these insights, considerable effort is still needed to elucidate how ligand binding induces receptor activation, what determines the specificity of AT1 receptor coupling to multiple G‐proteins and the in vivo role of receptor down‐regulation.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: TRANSGENIC RATS: TOOLS TO STUDY THE FUNCTION OF THE RENIN‐ANGIOTENSIN SYSTEM
Authors: Bader Michael , Ganten Detlev 
Published: June 2007

SUMMARY

The development of the transgenic technology for the rat allowed the evaluation of gene functions in the cardiovascular system in vivo. New insights have been gained particularly in the functions of the renin‐angiotensin system (RAS), as most transgenic rat models established so far carry genes of this system.
TGR(mREN2)27 is a rat harbouring the mouse Ren‐2 gene and exhibiting fulminant hypertension. The plasma RAS in this animal is down‐regulated; however, the tissue‐specific production of angiotensin II is activated (e.g. in the adrenal gland, the brain and the vessel wall). The physiological consequences of this activation, which finally leads to hypertension, can be studied in TGR(mREN2)27, rendering it a valuable tool in the functional analysis of tissue RAS.
TGR(hREN) and TGR(hAOGEN) carry the human genes for renin and angiotensinogen, respectively. In these animals the species‐specific interaction of the two proteins and the expression pattern of the genes can be studied. Furthermore, these animals can be used to test renin‐inhibitory drugs for use in antihypertensive therapy.
Further refinement of transgenic methodology (e.g. by the development of gene targeting in rats), should enhance our understanding of the functions of the RAS in cardiovascular regulation.
EFFECTS OF HYPERINSULINAEMIA ON RENAL FUNCTION AND THE PRESSOR SYSTEM IN INSULIN‐RESISTANT OBESE ADOLESCENTS
Authors: Miyazaki Y. , Shimamoto K. , Ise T. , Shiiki M. , Higashiura K. , Hirata A. , Masuda A. , Nakagawa M. , Iimura O. 
Published: June 2007

SUMMARY1. In the present study, using the euglycaemic hyperinsulinaemic glucose clamp technique, we investigated the effects of hyperinsulinaemia on sodium‐water metabolism and the pressor system in obesity, both of which have been reported to be closely associated with insulin resistance and/or hyperinsulinaemia.2. Sixteen obese young subjects and 24 non‐obese young subjects who were all normotensives, participated in this study. The 2h euglycaemic hyperinsulinaemic glucose clamp was performed in a fasting state. The mean glucose infusion rate needed to maintain a fasting blood sugar level (FBS) during the last 30 min of the clamp was used as an indicator of insulin sensitivity (M‐value). Before and after the clamp, the following parameters were measured: creatinine clearance (Ccr); urinary excretion of sodium (UNaV); fractional excretion of sodium (FENa); plasma renin activity (PRA); plasma aldosterone concentration (PAC) and plasma noradrenaline concentration (PNA).3. The M‐value was significantly lower in obese subjects compared with non‐obese subjects, although FBS and fasting immunoreactive insulin levels were similar in both groups. UNaV and FENa fell only in obese subjects during the clamp, while Ccr showed no significant change in either group. PNA and PRA increased significantly and PAC tended to increase in both groups.4. These results suggest that obese subjects have insulin resistance with respect to glucose metabolism, but that urinary sodium excretion and the pressor system remain insulin‐sensitive; the sensitivity of the sodium retaining action to hyperinsulinaemia was actually higher in obese subjects than in non‐obese subjects. Therefore, if compensatory endogenous hyperinsulinaemia was raised by insulin resistance, these two factors may lead to chronic sodium retention and pressor system stimulation and, in turn, to hypertension in obesity.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction SIGNALLING PATHWAYS ACTIVATED BY ENDOTHELIN STIMULATION OF RENAL CELLS
Authors: Nord Edward P 
Published: June 2007

SUMMARY1. Endothelin mediates its effects in a variety of renal cells via a multiplicity of intracellular signalling pathways.2. Stimulation of phosphatidylinositol‐specific phospholipase C (PI‐PLC), resulting in the activation of inositol trisphosphate and diacylglycerol, can be detected even at picomolar concentrations of peptide.3. Endothelin activation of cPLA2 is sensitive to ambient [Ca2+]i, is not contingent upon protein kinase C activation and is independent of PI‐PLC stimulation, being coupled to the endothelin receptor in a yet to be determined manner.4. Activation by endothelin of phosphatidylcholine‐specific phospholipase D is under the dual regulation of protein kinase C and [Ca2+]i, with protein kinase C being the major regulator and [Ca2+]i playing a secondary, modulatory role.5. Phosphatidylcholine‐specific phospholipase C (PC‐PLC) is stimulated by endothelin and accounts for the prolonged activation of diacylglycerol by this peptide. PC‐PLC activity is critically dependent upon [Ca2+]i, whereas protein kinase C plays no role in modulating the activity of this enzyme.6. Endothelin enhances the phosphorylation of protein tyrosine kinases, with evidence that phosphorylation of pp60 Src may be an important early event.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ROLE OF ENDOTHELIN IN RENAL FUNCTION AND DYSFUNCTION
Authors: Brooks David P 
Published: June 2007

SUMMARY1. Endothelin has significant effects on renovascular, glomerular and tubular function.2. Endothelin causes severe renal vasoconstriction, resulting in a decrease in renal blood flow and glomerular filtration rate.3. Endothelin can inhibit sodium reabsorption and, in the rat, vasopressin‐induced water transport.4. The endothelin receptor subtypes mediating renovascular and tubular effects of endothelin may differ between species.5. Renal endothelin production, metabolism and receptor binding is altered in a number of renal diseases, including acute and chronic renal failure and cyclosporine and radiocontrast nephrotoxicity.6. Endothelin receptor antagonists or antibodies can attenuate the severity or progression of a number of renal diseases.
ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT2 AND ENDOMETRIAL AT1 RECEPTORS ARE DOWN‐REGULATED DURING GESTATION
Authors: Nielsen AH , Schauser K. , Winther H. , Dantzer V. , Poulsen K. 
Published: June 2007

SUMMARY1. The aim of the present study was to characterize the angiotensin II (AngII) receptor subtypes in the porcine uterus and the variation of receptor densities and renin concentrations during gestation.2. In myometrium from non‐pregnant sows, the AngII receptors were almost exclusively AT2 receptors. During gestation, the AngII receptor density was decreased and the AT1 receptor became predominant in the last part of gestation as a result of a down‐regulation of the AT2 receptor.3. In the endometrium, the AT1 receptor was predominant both in non‐pregnant sows and throughout gestation. The AngII receptor density was decreased during gestation as a consequence of down‐regulation of the AT1 receptor.4. The renin concentrations in the myometrium and endometrium of pregnant sows did not differ from those in non‐pregnant animals.5. The finding of enzymatically active renin and high densities of AngII receptors in the porcine uterus is in accordance with a functional renin‐angiotensin system (RAS), which may be important for an increased vascular permeability and stimulated angiogenesis in early pregnancy and for contraction of the myo‐metrial smooth muscle cells during parturition. The predominance of ATi receptors in the endometrium of non‐pregnant sows differs from an earlier finding in non‐pregnant women, where AT2 receptors were predominant in the endometrium. This is in accordance with earlier studies, indicating species differences in the expression and possibly also the physiological roles of the RAS in reproductive tissues.