bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes
Authors: Lim Su Chi , Morgenthaler Nils G. , Subramaniam Tavintharan , Wu Yew Seng , Goh Siew Kheng , Sum Chee Fang
Published: May 2007

OBJECTIVE—Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel vascoactive factor, is deranged in subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Using a new immunoluminometric method, plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese subjects: healthy (n = 100, fasting plasma glucose [FPG] <5.6 mmol/l), impaired fasting glucose (IFG) (n = 60, FPG 5.6–6.9 mmol/l), and diabetic subjects with (n = 100) and without (n = 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quantified in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function.

RESULTS—We observed a stepwise increase in MR-proADM among the groups: healthy group mean ± SD 0.27 ± 0.09, IFG group 0.29 ± 0.13, diabetic group 0.42 ± 0.13, and diabetic nephropathy group 0.81 ± 0.54 nmol/l (diabetic vs. healthy and IFG groups, P = 0.04; and diabetic nephropathy group vs. all, P < 0.01). Statistical adjustment for sex, age, BMI, and blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (β = 0.11; P = 0.01), insulin resistance index (β = 0.20; P = 0.001), LDL cholesterol (β = 0.31; P < 0.001), and adiponectin (β = 0.33; P < 0.001) were significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with RCMP (r = 0.43, P = 0.002).

CONCLUSIONS—Plasma MR-proADM concentration was elevated in subjects with type 2 diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a role in the pathogenesis of diabetic vasculopathy.
Insulin Resistance Is Associated With Hypercortisolemia in Polynesian Patients Treated With Antipsychotic Medication
Authors: Poa Nicola R. , Edgar Paul F.
Published: May 2007

OBJECTIVE—Type 2 diabetes is more prevalent in the indigenous Polynesian population of New Zealand (Maori) than in Europeans. The aim of this study was to determine whether insulin resistance in Maori psychiatric patients was associated with antipsychotic treatment and to investigate the mechanism of an association.

RESEARCH DESIGN AND METHODS—Thirty adult Maori psychiatric patients receiving antipsychotic medication for >6 months and 30 healthy, age-, sex-, and BMI-matched control subjects were enrolled. Early morning fasting blood samples were analyzed for plasma levels of glucose, insulin, A1C, triglycerides, total cholesterol, IGF-1, cortisol, cortisol-binding globulin (CBG), and adiponectin.

RESULTS—The patient group had significantly higher median fasting insulin plasma levels than the control group (P = 0.002), which were independent of BMI, age, and sex. In addition, the patient group had significantly higher total cortisol (P = 0.03) and lower CBG levels (P = 0.004) than the control group, resulting in significantly higher levels of free cortisol (P = 0.004). The patient group was also significantly more hypoglycemic (P = 0.026) and hypertriglyceridemic (P = 0.028) than the control group. There was no significant difference in BMI, waist circumference, A1C, total cholesterol, IGF-1, or adiponectin levels between the two groups.

CONCLUSIONS—An increase in insulin resistance is seen in Maori psychiatric patients treated with antipsychotic medication. Therefore, Polynesian ethnicity should be considered in prescribing practice and general care of this group. In addition, the hypothalamic-pituitary-adrenal axis may have an important role in the mechanism by which this insulin resistance develops.
Relationship Between Metabolic Risk Factor Clustering and Cardiovascular Mortality Stratified by High Blood Glucose and Obesity
Authors: Kadota Aya , Hozawa Atsushi , Okamura Tomonori , Kadowak Takashi , Nakmaura Koshi , Murakami Yoshitaka , Hayakawa Takehito , Kita Yoshikuni , Okayama Akira , Nakamura Yasuyuki , Kashiwagi Atsunori , Ueshima Hirotsugu ,   for the NIPPON DATA Research Group
Published: May 2007

OBJECTIVE—Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity.

RESEARCH DESIGN AND METHODS—We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model.

RESULTS—During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (Ptrend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49–9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93–4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity.

CONCLUSIONS—Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk.
Severe Hypoglycemia and Smoking in a Long-Term Type 1 Diabetic Population
Authors: Hirai Flavio E. , Moss Scot E. , Klein Barbara E.K. , Klein Ronald
Published: May 2007

OBJECTIVE—The purpose of this study was to evaluate the relationship of severe hypoglycemia and smoking in a population-based cohort of individuals with long-term type 1 diabetes.

RESEARCH DESIGN AND METHODS—This was a cross-sectional analysis of the population-based cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The analyses in this report were limited to 537 type 1 diabetic individuals with complete data who participated in the last examination phase (2000–2001). Severe hypoglycemia was defined as having one or more episodes of loss of consciousness or overnight hospitalization attributable to hypoglycemia in a 1-year period before the examination.

RESULTS—The prevalence of severe hypoglycemia in this population was 14.3%. In univariate analysis, current smokers had a greater chance of having severe hypoglycemia compared with never smokers (odds ratio 2.40 [95% CI 1.30–4.40]). When we controlled for relevant confounders such as age, sex, A1C, waist-to-hip ratio, orthostatic hypotension, alcohol consumption, intensive insulin treatment, past history of severe hypoglycemia, and late complications of diabetes (nephropathy, neuropathy, and retinopathy), the association remained statistically significant, with current smoking presenting ∼2.6 times greater odds of developing severe hypoglycemia.

CONCLUSIONS—Current smokers with type 1 diabetes have higher odds of severe hypoglycemia episodes.
Racial and Ethnic Variation in Access to Health Care, Provision of Health Care Services, and Ratings of Health Among Women With Histories of Gestational Diabetes Mellitus
Authors: Kim Catherine , Sinco Brandy , Kieffer Edith A.
Published: May 2007

OBJECTIVE—The purpose of this study was to assess racial/ethnic variation in access to health care, use of particular health care services, presence of cardiovascular risk factors, and perceptions of health and impairment among women at risk for type 2 diabetes because of their histories of gestational diabetes mellitus (hGDM).

RESEARCH DESIGN AND METHODS—We performed a cross-sectional study using the 2001–2003 Behavioral Risk Factor Surveillance System, a national population-based, random sample telephone survey. We assessed access to health care, use of family planning, measurement and elevation of cholesterol, elevation of blood pressure, and respondents’ perceptions of health and impairment among women aged 18–44 years with hGDM (n = 4,718). Multivariate models adjusted for sociodemographic characteristics, BMI, presence of children in the household, and current smoking.

RESULTS—Outcome measures were suboptimal across racial/ethnic groups. Approximately one-fifth of the overall population reported no health insurance, cost barriers to physician visits, and no primary care provider. One-quarter had no examination within the past year, and almost one-fifth reported no family planning and elevated cholesterol levels. Latinas were the most disadvantaged, with 40% reporting no health insurance and no primary care provider and one-fourth reporting suboptimal perceptions of health. Asian/Pacific Islanders were the most advantaged in terms of health care access, cholesterol and blood pressure elevation, and impaired physical health. Racial/ethnic differences in health care use and presence of risk factors were not entirely explained by health care access or other covariates.

CONCLUSIONS—Significant racial/ethnic variation exists among women with hGDM for access to and use of health care, presence of risk factors, and perceptions of health.
High sensitivity photonic crystal pressure sensor
Authors: Biallo D. , De Sario M. , D’Orazio A. , Marrocco V. , Petruzzelli V. , Vincenti M. A. , Prudenzano F. , Stomeo T. , Grande M. , Visimberga G. , Cingolani R. , De Vittorio M.
Published: May 2007

A two-dimensional photonic crystal microcavity coupled to a photonic crystal waveguide is proposed to realise a high sensitive pressure sensor, designed on a GaAs membrane. A theoretical model is developed to evaluate the change of the refractive index induced by the application of a force onto a sensing surface. A linear calibration curve is obtained relating the resonant drop position to the applied pressure.
Ein Vergleich verschiedener Lichtmessmethoden in Buchennaturwäldern Sloweniens aus verjüngungsökologischer Sicht | A comparison of solar radiation estimation methods in old-aged beech forests in Slovenia from the point of view of ecological regeneration
Authors: Diaci Jurij , Thormann Jean-Jacques
Published: May 2007

In 1999 we compared four efficient and simple methods for estimating the radiation climate in forests:hemispherical photography, horizontoscope, LAI-2000 and instantaneous measurements of percentage of above-canopy photosynthetic photon flux density (%PPFD). 64 measurements were taken 1.0 m above the ground within four gaps and under the closed canopies of two deeply shaded oldgrowth beech forests.
Umwandlungs- und Aufforstungsmassnahmen in vernachlässigten Kastanien-Stockausschlagwäldern im Tessin – Aufwendungen und Kosten | Transformation and afforestation measures in neglected chestnut coppice stands in the canton of Tessin – expenditures and costs
Authors: Ott Ernst
Published: May 2007

The attack of the chestnut blight (Cryphonectria parasitica) on chestnut coppice stands on the southern side of the Swiss Alps started to take on epidemic proportions in 1948. At the time,catastrophic experiences in America raised fears that it would lead to the total destruction of the chestnut. In consequence a wide-ranging transformation programme was initiated in the canton of Tessin. For want of relevant practical experience all promising species were planted using the then existing planting and silvicultural techniques for systematic, high-quality wood production. However, the existing infrastructure did not allow for a detailed control of expenditure for the measures taken. Starting in 1973, within a teaching-forest project, the Institute of silviculture of the ETH Zurich made control possible. In this report we present and analyse the measures applied to 17 parcels of land, nine of which were transformed and eight afforested. From today’s point of view the total cost was disproportionately high, sometimes more than 1500 hours per hectare in the first 15 to 20 years. Taking developments in wood prices and forest management costs since then into consideration we conclude that indiscriminate planting is not to be recommended, especially in view of the fact that the chestnut blight turned out to be relatively harmless thanks to the phenomenon of «hypo-virulence». Finally, we discuss alternative silvicultural measures for chestnut coppice stands.
Die waldpolitische Öffnung: Ein Holzweg? | The opening-up of forest policy:a wrong turning?
Authors: Hostettler Martin
Published: May 2007

The paper is a contribution towards the fundamental discussion on the future of the Swiss forest economy and presents the possible effects of a far-reaching liberalisation. We develop the basis for a liberal program with the transfer of more responsibility to forest owners, the abolition of subsidies and the withdrawal of civil servants from forest management. The program looks at the importance of clear and stable property rights and explains private provision of public expectations on the forest, taking the new understanding of bureaucracy's role into consideration. Distortion of competition and insufficient time prove to be obstacles to piecemeal reform. The struggle for profit, competitive attitudes or economic theory, research and practice can all contribute to an opening. The spontaneous nature of the liberal order means that the relevance of domestic wood production remains open.
Stockausschlag nach Mondphase | Coppice shoots according to lunar phases
Authors: Zürcher Ernst
Published: May 2007

Within the framework of «Tree biology/Wood characteristics with regard to lunar phases» data of a recurrent calender were critically analysed. This minor experiment tested the predicted scarcity of coppice shoots after felling on two recommended dates by comparison with data collected on «nearby dates». It transpires that a «lunar effect» was produced for only one tree species on one of the two given dates and that this was the contrary to what was claimed (a promotion of the coppice shoots instead of «no coppice shoots»).
Rat model for investigating ACTH-independent angiotensin-induced aldosterone secretion
Authors: Roesch Darren M , Ying Tian  , Verbalis Joseph G , Sandberg Kathryn
Published: May 2007

Study of the acute effects of angiotensin II (Ang II) on aldosterone secretion has been hindered by the confounding influence of Ang II-induced adrenocorticotropic hormone (ACTH) secretion on aldosterone secretion, and by the fact that when laboratory rats are fed standard laboratory chows that are high in sodium, the adrenal is only minimally responsive to Ang II. In this study, we report the development of a model of Ang II-induced aldosterone secretion in NaCl-deprived, dexamethasone (DEX)-treated rats. This model allows the observation of (a) a high magnitude of Ang II-induced aldosterone secretion, (b) a return of plasma aldosterone levels to baseline after stimulation, and (c) aldosterone secretion without the potentially confounding influence of ACTH stimulation.
Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury
Authors: Lemay Jacinthe , Hamet Pavel , deBlois Denis
Published: May 2007

Smooth muscle cell (SMC) apoptosis is transiently increased at the onset of the regression of aortic hypertrophy in spontaneously hypertensive rats (SHR) treated with the angiotensin II AT1 antagonist losartan. We postulated that losartan induction of SMC apoptosis contributes to suppression of neointimal hyperplasia after vascular injury. Losartan or placebo treatment was initiated two days before balloon injury in the SHR aorta. Compared with time-matched placebo, losartan decreased neointimal cross-sectional area at Days 5 and 10 after injury by 50% and 64% respectively, without affecting medial mass. At Day 10, losartan significantly decreased SMC number (by 56%) in the neointima, but not in the media. DNA synthesis was significantly inhibited at Day 5 but not at Day 10. Losartan significantly increased aortic DNA fragmentation by 2.6- and 4.1-fold, at Days 5 and 10, respectively. In situ labeling of SMC with terminal deoxynucleotidyltransferase revealed significant 61% and 68% increases in apoptotic SMC at Days 5 and 10 with losartan treatment, predominantly in the neointima. Thus, losartan suppressed neointima formation in part by the induction of SMC apoptosis, which may be dissociated from the inhibition of DNA synthesis. Therefore, losartan-induced SMC apoptosis may be a potential therapeutic approach to control occlusive vascular disorders.
Molecular mechanism(s) of insulin action on the expression of the angiotensinogen gene in kidney proximal tubular cells
Authors: Wu Xiao-Hua , Xing Chen  , Zhang Shao-Ling , Li Pang  , To Catherine , Wang Tian-Tian , Hohman Thomas C , Filep Janos G , Chan John SD
Published: May 2007

To investigate the molecular mechanism(s) of insulin action on the expression of the angiotensinogen (ANG) gene in kidney proximal tubular cells, we constructed a fusion gene, pOGH (hANG N-1064/+27), containing the 5'-flanking regulatory sequence of the human ANG gene fused with the human growth hormone (hGH) gene as a reporter and stably integrated the fusion gene into the opossum kidney (OK) cell genomes. The level of expression of pOGH (hANG N-1064/+27) was quantified by the amount of immunoreactive hGH secreted into the medium. The addition of a high level of D(+)-glucose (25 mM) or phorbol 12-myristate 13-acetate (PMA, 10-7 M) stimulated the expression of the fusion gene in OK cells. The stimulatory effect of glucose (25 mM) was blocked by insulin and tolrestat (an inhibitor of aldose reductase). Tolrestat also inhibited the increase of cellular DAG and PKC activity stimulated by 25 mM glucose. While insulin did not affect the cellular DAG and PKC activity, it did block the stimulatory effect of high glucose (25 mM) and PMA on the expression of the fusion gene. Finally, PD98059 (an inhibitor of mitogen-activated protein kinase kinase (MEK)) enhanced the stimulatory effect of high levels of glucose and blocked the inhibitory effect of insulin on the expression of the fusion gene as well as on the phosphorylation of MEK and mitogen-activated protein kinase (MAPK). In contrast, Wortmannin (an inhibitor of phosphatidylinositol-3-kinase) did not block the inhibitory effect of insulin on the ANG gene expression. These studies demonstrate that the action of insulin, blocking the stimulatory effect of a high level of D(+)-glucose (25 mM) on the ANG gene expression is mediated, at least in part, via the 5'flanking region of the ANG gene and MAPK signal transduction pathway.
Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan
Authors: Núñez Antonio , Gómez Juan , Zalba Luis Rico , Montón Mercedes , Jiménez Ana , Velasco Sandra , López-Blaya Almudena , Celdrán Uriarte Angel , Casado Santos , López-Farré Antonio
Published: May 2007

A recent study has shown that losartan, an AT1-receptor antagonist, interacts with thromboxane A2(TxA2)/prostaglandin H2(PGH2) receptors in human platelets. The aim of the present study was to analyse the ability of different angiotensin II (Ang II) AT1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers and were stimulated with the thromboxane A2analogue, U46619 (10-6mol/L). U46619-stimulated platelet activation was significantly reduced by losartan in a dose-dependent manner. Only maximal doses of valsartan (5x10-6mol/L), reduced U46619-induced platelet activation. The active form of candesartan cilexetil, candesartan (CV-11974), failed to modify platelet activation. Losartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed to a lesser extent with valsartan but not with CV-11974. These results suggest that, whilst some AT1-receptor antagonists reduce TxA2-dependent human platelet activation, it is not a feature common to all AT1antagonists.
Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-ε in acutely reperfused myocardial infarction in the dog
Authors: Yi Xu  , Menon Vijayan , Jugdutt Bodh I
Published: May 2007

To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT1) receptor blockade involves Ang II type 2 (AT2) receptor expression and protein kinase C-ε (PKCε) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT1/AT2-receptor expression, IP3R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKCε proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT1-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT1-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT1-receptor antagonists decreased infarct size. Importantly, MI decreased AT1-receptor and AT2-receptor expression while MI after AT1-receptor antagonism increased AT1-receptor (mRNA, not protein) and AT2-receptor (mRNA and protein) expression as well as IP3R and PKCε proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT1-receptor antagonism involves enhanced AT2-receptor expression and possibly downstream signalling through IP3R, PKCε and cGMP.
Losartan reduces collagen content and intimal thickening of iliac arteries after balloon injury in rabbits
Authors: Jianhua Zhu  , Danchen Gao
Published: May 2007

Intimal thickening and formation of extracellular matrix are parts of the repair process after vascular injury. Similar processes occur after coronary angioplasty. Prior studies have shown that losartan inhibits intimal thickening in rat carotid arteries following balloon injury. However, the effects of losartan in reducing the collagen content of arteries after balloon injury have not been examined. The objectives of this study were to determine the change in collagen content after balloon injury and to analyse the mechanisms of reduction of collagen content and intimal thickening. Losartan (15 mg/kg/d) was administered orally from six days before to eight weeks after balloon injury in rabbits. Collagen content was measured histologically by the use of circularly polarised images of picrosirius red-stained sections. Collagen content in arterial intima was found to be significantly lower in the losartan-treated group (n=12) than in the control group (n=12) (21.6%±5.2% vs. 43.8%±7.6%, p<0.01). Losartan reduced the collagen content in arterial intima by 50.7% area fraction compared with that of control. The morphological observation showed that the intimal area and intimal-to-medial area ratio in the losartan-treated group were significantly less than in the control group (0.27±0.13mm 2 vs. 0.52±0.29 mm2, 0.55±0.21 vs. 0.97±0.25, respectively, p<0.05). These data indicate that losartan reduces vascular collagen content and inhibits intimal thickening after balloon injury. The results also suggest that collagen accumulation in the intima may be an important factor in the development of the stenotic lesion and that the use of losartan may have therapeutic value to prevent stenosis after balloon injury.
Valsartan and the renin-angiotensin-aldosterone system: Blood pressure control and beyond
Authors: Dahlöf Björn
Published: May 2007

Patients treated for hypertension are still at significantly elevated risk for cardiovascular complications when compared with normotensive patients, even when on antihypertensive therapy. In all fairness though, a majority of these patients have uncontrolled blood pressure. Blocking the renin-angiotensin-aldosterone system (RAAS) prevents or reverses cardiac remodelling and improves prognosis in cardiovascular disease beyond the effects on blood pressure (BP). Valsartan acts by selectively blocking the AT1-receptor and shows similar efficacy and improved tolerability compared with ACE inhibitors. This drug may provide additional benefits in controlling the cardiovascular complications of hypertension. Results of large clinical trials with valsartan, such as VALUE, Val-HEFT, VALIANT and ABCD-2V, are eagerly awaited.
Rationale for angiotensin II receptor blocker therapy in chronic heart failure
Authors: Cohn Jay N
Published: May 2007

Inhibiting the synthesis of angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) inhibitor treatment has long been established as the recommended therapy for heart failure (HF). As ACE inhibitors are only partially effective in blocking the formation of Ang II, additional treatment with selective Ang II receptor blockers (ARBs) promise additional benefits in patients with H F. This hypothesis is currently being evaluated in Val-HeFT, a large-scale, randomised, double-blind, placebo-controlled study on the effects of adding the highly selective ARB valsartan to usual therapy (diuretics, digoxin, beta-blockers, ACE inhibitors) for HF treatment.
Angiotensin receptor blocker selectivity at the AT1- and AT2-receptors: conceptual and clinical effects
Authors: Unger Thomas , Sandmann Steffen
Published: May 2007

The advent of specific angiotensin II (Ang II) receptor blockers (ARBs) some ten years ago has provided substantial information on the specific actions of the AT1- and AT2-receptors. Most of the early research concentrated on the AT1-receptor, and the actions and biological roles of the AT2-receptor are much less well characterised. The AT2-receptor is involved in the inhibition of cell proliferation, and in cell differentiation and development, regeneration and apoptosis. By raising local Ang II concentrations at the AT2-receptor, selective blocking of the AT1-receptor may therefore have beneficial effects. This concept may be important for antihypertensive therapy and in cardiovascular disease in general.
The losartan renal protection study — rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)
Authors: Brenner Barry M , Cooper Mark E , de Zeeuw Dick , Grunfeld Jean-Pierre , Keane William F , Kurokawa Kiyoshi , McGill Janet B , Mitch William E , Parving Hans Henrik , Remuzzi Guiseppe , Ribeiro Arthur B , Schluchter Mark D , Snavely Duane , Zhang Zhongxin , Simpson Roger , Ramjit Denise , Shahinfar Shahnaz , RENAAL Study Investigators
Published: May 2007

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.
The pharmacological potency of various AT1 antagonists assessed by Schild regression technique in man
Authors: Belz Gustav G , Breithaupt-Grögler Kerstin , Butzer Raunhild , Fuchs Winfried , Hausdorf Christian , Mang Christian
Published: May 2007

Rationale A quantitative technique was used to compare the pharmacological potency in healthy volunteers of angiotensin II receptor antagonists (AIIA): candesartan cilexetil, losartan, irbesartan, valsartan, and telmisartan.

Methods In a randomised, double-blind, parallel-group (4x12 subjects) study, single oral doses of candesartan cilexetil 4, 8 and 16 mg, losartan potassium 25, 50 and 100 mg, valsartan 40, 80 and 160 mg, and irbesartan 75, 150 and 300 mg were administered on three consecutive days. Telmisartan 20, 40 and 80 mg was similarly evaluated in 12 volunteers in an open amendment. Angiotensin II (Ang II) antagonistic effects were determined in vivo from rightward shifts in Ang II dose-response curves for diastolic blood pressure (BP) and dose ratios were calculated. Apparent Ki-doses, i.e. doses (in mg) required to induce a two-fold shift in Ang II dose-response curves (equivalent to approx. 50% blockade of receptors) were determined, using Schild regression analysis.

Results All treatments dose-dependently attenuated increases in diastolic BP induced by infusion of exogenous Ang II. Candesartan cilexetil appeared to have a more pronounced increase in effect following cumulative dosing. At 24 hours, apparent K i-doses were: candesartan cilexetil 6 mg, irbesartan 123 mg, valsartan 93.5 mg, and telmisartan 54 mg. It was not possible to determine an apparent Ki-dose for losartan at 24 hours.

Conclusion Consistent with results from experimental pharmacology, candesartan cilexetil displayed the highest pharmacological potency (i.e. antagonistic activity per mg substance) of the AIIAs tested. Apparent Ki-doses at 24 hours were within the dose range recommended for clinical use in patients with hypertension.
Increased serum angiotensin-converting enzyme activity and plasma angiotensin II levels during pregnancy and postpartum in the diabetic rat
Authors: van Dijk David Jonathan , Boner Geoffrey , Giler Shaul , Erman Arie
Published: May 2007

Objective The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, electrolyte balance and renal function in normal human pregnancy. The present study was designed to assess various components of the RAS and renal function during pregnancy and immediately after pregnancy in the streptozotocin (STZ)-diabetic rat.

Methods Pregnant Wistar rats were allocated to three groups: I- control, non-diabetic rats (n=24), II- STZ-diabetic rats (STZ 55 mg/kg body weight, i.v. on day 10 of pregnancy, n=24), III- diabetic rats, as above, treated with insulin (4 units/day, s.c. n=21). On days 17—18 of pregnancy, or within 24 hours after delivery, the rats were sacrificed and the various components of the RAS were determined.

Results Urinary protein excretion (UP) and creatinine clearance (CCr) were greater in group II, four days after STZ, than in group I (UP: I-7.6±2.8, II-18.6±6.3 mg/24-hour, p<0.001, CCr: I-1.04±0.33, II-2.38±0.7 ml/minute, p<0.001). Mean (±SD) serum angiotensin-converting enzyme (ACE) activity and plasma angiotensin II (Ang II) levels at days 17—18 of pregnancy were greater in the untreated diabetic rats than in control pregnant rats (ACE: 163±18 vs . 111±21 nmol/ml/minute, p<0.001, Ang II: 115±45 vs. 43±10 pg/ml, p<0.005). Postpartum serum ACE activity and plasma Ang II levels were greater in group II (ACE: I-123±14, II-142±24, III-108±21 nmol/ml/minute, p<0.01, Ang II: I-56±38, II-148±62, III-38±17 pg/ml, p<0.001). ACE activity in the lung was greater, whereas the activity in the renal cortex was less, in group II than in group I. Kidney weight in untreated diabetic rats was greater than in the other two groups.

Conclusion Increased serum ACE activity during pregnancy and postpartum in the untreated diabetic rat is associated with enhanced serum Ang II levels, which may contribute to increased protein excretion and renal hypertrophy.
Renin-angiotensin blockade improves renal cGMP production via non-AT2-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat
Authors: Uhlenius Nina , Vuolteenaho Olli , Tikkanen Ilkka
Published: May 2007

Background

To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS) blockade.

Methods

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT 1-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP), urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.

Results

Captopril and L-158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT1 -receptor binding in the kidney was inhibited to about 40% of the control value after administration of L-158,809. The AT2-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.

Conclusion

Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT1-receptor antagonism on cGMP production was not mediated by AT2-receptor-dependent mechanisms, since renal AT2-receptor binding density was suppressed following treatment with L-158,809. AT1-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.
Comparison of the effects of antihypertensive treatment with angiotensin II blockade and beta-blockade on carotid wall structure and haemodynamics: protocol and baseline demographics
Authors: Ariff Ben , Stanton Alice , Barratt Dean , Augst Alex , Glor Fadi , Poulter Neil , Sever Peter , Yun Xu  , Hughes Alun , Thom Simon AMcG
Published: May 2007

Several systemic factors have been shown to contribute to the acceleration of large vessel atheroma. Correction of these factors leads to a reduction in the progression of plaque formation and associated arterial wall thickness. Atheroma remains, however, a focal disease, developing at characteristic sites within the arterial tree. These sites are typically at areas of vessel branching or marked curvature, and correspond to regions of high tensile stress and low sheer stress, leading to the hypothesis that local haemodynamic factors and vessel wall mechanics potentiate the focal development of atheroma.

Current assessment of vascular haemodynamics suffers from an inability to handle complex flow, and does not allow accurate determination of locally varying flow, and shear stress patterns. The application of computational fluid dynamic (CFD) flow simulation techniques to ultrasound and local pressure data, however, allows a comprehensive, non-invasive appraisal of haemodynamic flow parameters to be performed.

The Candesartan cilexetil and Atenolol Carotid Haemodynamic Endpoint Trial (CACHET) study compares the effects of two antihypertensive regimens, one β-blocker-based, the other angiotensin receptor blocker based, on carotid intima-media thickness. The collection of ultrasound and pressure data on each subject provides a unique opportunity to apply these data to the CFD model to study the effects of these antihypertensive regimens on local fluid dynamics. This will lead to a greater understanding of the relationship of these factors to atheroma formation and regression.
High plasma adrenomedullin concentrations in patients with high-renin essential hypertension
Authors: Letizia Claudio , Subioli Stefano , Cerci Sabrine , Caliumi Chiara , Verrelli Cristiana , Delfini Enrica , Celi Massimiliano , Scuro Luigi , D'Erasmo Emilio
Published: May 2007

Adrenomedullin (AM) is a novel peptide, first isolated from human phaeochromocytoma, which elicits a long-lasting vasorelaxant activity. Recently, it has been reported that endothelial cells produce AM and that immunoreactive AM plasma levels may be elevated in human arterial hypertension, although the exact pathophysiological role of AM remains to be established.

The aim of our study was to determine the relationship between the components of the renin-angiotensin-aldosterone system (RAAS) and plasma AM levels in patients with low-, medium- or high-renin essential hypertension.

The study groups included 10 patients with low-renin essential hypertension (average age 42 15 years), nine patients with medium-renin essential hypertension (46 13 years), 11 patients with high-renin essential hypertension (42 14 years) and 12 healthy subjects (43 11 years).

Our results demonstrated that the mean AM values of all patients with essential hypertension were 10.85 3.14 pg/ml; there was a statistical correlation (r=0.705; p<0.001) between plasma renin activity (PRA) and AM levels in hypertensives.

In patients with high-renin essential hypertension, plasma AM levels (14.2 2.2 pg/ml) were significantly higher (p<0.001) than those of healthy subjects (8.7 2.1 pg/ml), patients with medium-renin essential hypertension (8.5 1.4 pg/ml), and patients with low-renin essential hypertension (9.1 1.5 pg/ml). There was no statistical difference in AM concentrations between medium- and low-renin hypertensive patients. In conclusion, we have found that, in hypertensive patients, plasma AM levels were increased only in high-renin individuals, suggesting a role of AM in this particular form of human essential hypertension.
Review: Renin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management
Authors: Chiong Jun R , Miller Alan B
Published: May 2007

The renin-angiotensin system (RAS) and dyslipidaemia have been shown to be involved in the genesis and progression of atherosclerosis. Manipulation of the RAS has been effective in modifying human coronary artery disease progression. Similarly, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or `statins' have been shown to reduce cholesterol and lower cardiovascular events in primary and secondary prevention trials in coronary artery disease. In addition to their primary mode of action, statins and blockers of the RAS possess common additional properties that include restoration of endothelial activity and inhibition of cellular proliferation. This article reviews the current data on the common properties of these classes of drugs in which the beneficial effects extend beyond their antihypertensive and lipid-lowering properties.
Involvement of the AT2-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission
Authors: Balt Jippe C , Mathy Marie-Jeanne , Nap Alex , Pfaffendorf Martin , van Zwieten Pieter A
Published: May 2007

Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionallylocated AT1-receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang II and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang II is a class effect of all AT1-receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT2-receptor is involved in this `upturn' of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1—60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT2blocker, PD 123319 (0.5 mg/kg +50 µg/kg/min). Additionally, the effect of the combined (non-selective) AT1/AT2-receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model.

The stimulation-induced increase in diastolic blood pressure (DBP) could be dose-dependently reduced by irbesartan. Co-infusion with PD 123319 increased the sympatho-inhibitory potency of irbesartan, possibly through displacement of irbesartan from plasma protein binding sites. The U-shaped dose-response relationship observed with irbesartan, which is illustrative for other ARBs in this model, was not observed when PD 123319 was co-administered with irbesartan, nor with the non-selective AT1/AT2blocker, saralasin. PRA-levels increased from 111.0±17.8 to 198.7±22.2 ng/ml/hour after administration of irbesartan. PRA-levels did not differ when measured after the three highest doses of irbesartan.

Conclusions The present findings indicate a facilitatory role for the AT2-receptor, which is unmasked by the highest dose of irbesartan. Different plasma Ang II-levels are unlikely to have caused the less than maximal inhibition after the highest dose of irbesartan.
Comparative effects of aspirin with ACE inhibitor or angiotensin receptor blocker on myocardial infarction and vascular function
Authors: Zhu Bo-qing , Sievers Richard E , Browne Amanda EM , Lee Randall J , Chatterjee Kanu , Grossman William , Karliner Joel S , Parmley William W
Published: May 2007

Objectives

We previously showed that an angiotensin-converting enzyme inhibitor (captopril) or an angiotensin receptor blocker (losartan) reduced infarct size and improved endothelial function in a rat model of ischaemia-reperfusion. The present study was undertaken to see if aspirin (ASA) antagonised the beneficial effects of captopril or losartan.

Methods

One hundred and fourteen Sprague-Dawley rats were randomised into six groups; Control, ASA, captopril, losartan, ASA+captopril, and ASA+losartan. ASA, captopril or losartan were given at a concentration of 40 mg/kg/day in drinking water. After six weeks of pre-treatment, the rats were subjected to 17 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion, with haemodynamic and ECG monitoring. During the reperfusion period, the effective refractory period (ERP), ventricular fibrillation threshold (VFT) and bleeding time (BT) were measured. In fresh aortic rings precontracted with phenylephrine, endothelium-dependent and -independent relaxations were assessed using

acetylcholine and nitroglycerin. Results

Haemodynamic changes were not different between the groups. Serum ASA concentrations were 0.5, 1.1 and 0.6 mg/dl in the ASA, ASA+captopril and ASA+losartan groups, respectively, and BT was prolonged (p<0.01). ASA alone reduced endothelium-dependent relaxation (-29± 8 vs. -69±11%, p<0.01), but did not change endothelium-independent relaxation. ASA did not affect endothelial relaxation induced by acetylcholine in the presence of either captopril or losartan. Angiotensin I and ERP were elevated by captopril and losartan. Angiotensin II and VFT were elevated by losartan. ASA with captopril, captopril and losartan equally reduced infarct size, compared with control (39±3, 39±4 and 39±5 vs. 53±3%, all p<0.05).

Conclusions

Captopril and losartan had similar cardiovascular protective effects in a rat model of ischaemia-reperfusion. Aspirin did not attenuate the cardiovascular protective effects of captopril or losartan.
No involvement of the AT2-receptor in angiotensin II-enhanced sympathetic transmission in vitro
Authors: Nap Alexander , Balt Jippe C , Pfaffendorf Martin , van Zwieten Pieter A
Published: May 2007

Angiotensin II (Ang II) enhances sympathetic neurotransmission via AT1-receptors located on sympathetic nerve terminals. We recently demonstrated that inhibition of Ang II-mediated facilitation in the pithed rat by irbesartan resulted in a U-shaped dose response curve, which was not observed when PD 123319, at a concentration that selectively blocks the AT2-receptor, was co-administered. Hence, the irbesartan-mediated `upstroke' might be explained by the involvement of the AT2-receptor after AT1blockade with high-dose irbesartan. In the present study, we further investigated the possible role of the AT2-receptor in Ang II-mediated facilitation in vitro.

We studied the effect of the AT2-receptor antagonist PD 123319 (10 nM) on Ang II-enhanced sympathetic outflow evoked by electrical field stimulation (EFS) in the rat isolated inferior vena cava. Additionally, we investigated the effect of the AT1-receptor blocker irbesartan (0.1 nM—1 µM) on the sequelae of Ang II-enhanced, EFS-evoked sympathetic nerve traffic in the presence or absence of PD 123319 (10 nM).

PD 123319 did not influence Ang II-enhanced sympathetic outflow. Irbesartan dose-dependently attenuate Ang II-augmented transmitter release (pIC507.99±0.03), whereas no U-shaped concentrationresponse relationship for irbesartan was observed. Co-administration of PD 123319 with irbesartan proved unable to influence Ang II-mediated facilitation differently compared with irbesartan alone. The experimental observations indicate that the AT2-receptor is not involved in Ang II-mediated enhancement of sympathetic nerve traffic in the present in vitro study.
The Pickering Lecture British Hypertension Society, 10th September 2002
Authors: Harrison David G , Hua Cai  , Landmesser Ulf , Griendling Kathy K
Published: May 2007

An elevation in angiotensin II (Ang II) levels is a common occurrence in a diverse number of cardiovascular diseases including hypertension, hypercholesterolaemia, atherosclerotic coronary artery disease, left ventricular hypertrophy (LVH), heart failure and diabetes. An important effect of Ang II is activation of the NAD(P)H oxidase, a major source of reactive oxygen species (ROS) production by vascular cells. This increase in cellular ROS contributes to the pathogenesis of vascular disease by altering endothelial cell function, enhancing smooth muscle cell growth and proliferation, stimulating inflammatory proteins, including macrophage chemoattractant agents, growth factors and cytokines, and modulating matrix remodelling. Studies of genetically-altered mice have unequivocally shown that activation of the NAD(P)H oxidase by Ang II contributes to hypertension, LVH and atherosclerosis. Furthermore, increasing evidence suggest that the NAD(P)H oxidase contributes to human disease, suggesting that it is a potential target for future therapeutic intervention.