bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of the addition of losartan on uric acid metabolism in patients receiving indapamide
Authors: Nikas Spyros , Rizos Evangellos , Milionis Haralampos , Bairaktari Eleni , Kalaitzidis Rigas , Siamopoulos Kostas , Elisaf Moses
Published: May 2007

Objective A number of adverse metabolic effects are associated with indapamide administration, including an increase in serum uric acid levels. It has been reported that losartan can significantly decrease serum uric acid levels. However, there are no data on the effects of combination therapy of losartan with indapamide on uric acid metabolism.

Methods We studied 20 hypertensive patients in whom serum metabolic parameters, including uric acid levels in serum and urine, were studied before and after eight weeks of indapamide administration (2.5 mg once daily) as well as eight weeks after combination treatment with indapamide (2.5 mg once daily) and losartan (50 mg/day).

Results Indapamide evoked a significant decrease in systolic and diastolic blood pressure from a mean value of 157±12 mmHg/96±10 mmHg to a mean value of 139±14 mmHg/92±5 mmHg (p<0.01 for both comparisons). However, a significant increase in serum uric acid levels was noticed after indapamide administration (from a mean value of 4.9±1.6 mg/dl to a mean value of 5.9±1.2 mg/dl, p<0.01), associated with a decrease in the fractional excretion of uric acid (from a mean value of 9±5% to a mean value of 7±5.5%, p<0.05). The addition of losartan caused a further decrease in blood pressure from a mean value of 139±14 mmHg/92±5 mmHg to a mean value of 120±15 mmHg/84±4 mmHg (p<0.01 for both comparisons). This was followed by a significant decrease in serum uric acid levels to 5±1.1 mg/dl (p<0.01) due to a substantial increase in fractional urate excretion (from 7±5.5 to 8.7±6%, p<0.05).

Conclusion The addition of losartan could offset the hyperuricaemic effect of indapamide administration.
Improving the prognosis of diabetic patients: Evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB) therapy
Authors: Bedigian Martin P
Published: May 2007

The ABCD (Appropriate Blood Pressure Control in Diabetes) and ABCD-2V (Part 2 with Valsartan) are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP) control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM). The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB) and an angiotensin-converting enzyme (ACE) inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB) valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.
Acute effects of ACE inhibition on coronary endothelial dysfunction
Authors: Nickenig Georg , Stäblein Alexander , Wassmann Sven , Wyen Christoph , Müller Cornelius , Böhm Michael
Published: May 2007

The prerequisite of atherosclerosis, endothelial dysfunction, is characterised by impaired endothelium-dependent vasodilation caused by the reduced bioavailibility of nitric oxide (NO). In order to assess the role of acute ACE inhibition in this setting, coronary arterial endothelial function was quantified following acute intracoronary administration of the angiotensin-converting enzyme (ACE) inhibitor quinapril. Twenty-one patients with non-limiting coronary artery disease were studied before and after acute intracoronary administration of 10 mg quinapril. Nine patients received pre-treatment with the angiotensin AT1-receptor antagonist losartan (2x50 mg, p.o.). Coronary cross-sectional diameter was measured via quantitative angiography and microvascular reaction was investigated by intracoronary Doppler flow measurement during intracoronary infusion of 0.1 to 10 µmol/l acetylcholine. Quinapril acutely improved endothelial dysfunction on the macro- as well as the microvascular level. Losartan did not alter macrovascular function but facilitated microvascular endothelial function. Acute quinapril application led to no further improvement of endothelial dysfunction in patients pre-treated with losartan.

Acute quinapril infusion improved endothelial function in patients with coronary heart disease. Treatment with the AT1-receptor antagonist losartan led to a slight improvement in microvascular endothelial function, but pre-treatment with losartan blunted the vascular effect of quinapril, suggesting that the combination of ACE inhibition and AT1-receptor antagonism may not exert a synergistic benefical impact on the coronary vasculature.
Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man
Authors: Hollenberg Norman K , Osei Suzette Y , Lansang M Cecilia , Price Deborah A , Fisher Naomi DL
Published: May 2007

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30—40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165±14 mL/min/1.73m 2) significantly exceeded the response to captopril (118±12 mL/min/1.73m 2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97±20 mL/min/1.73m2) also significantly exceeded the response to captopril on the same diet (30±15 mL/min/1.73m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet, when compared with the response to captopril, suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60—70% range.
Effect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade
Authors: Tong Chuang Feng  , Wang Yui Ying  , Ren Jang Hua  , Ji Yale Y , de Gasparo Marc
Published: May 2007

The effects of the specific angiotensin II (Ang II) AT1receptor blocker valsartan on events related to restenosis were investigated in rabbits after common carotid balloon injury. Six animals were given valsartan from two days prior to injury until 14 days post-injury. Three control groups (n=6 in each group) were either sham-operated, untreated or treated with the angiotensin-converting enzyme (ACE) inhibitor, captopril. Both ACE inhibition and AT1-receptor blockade had marked effects on plasma levels of endothelin ET1, thromboxane TXB2 and 6-keto-PGF1-alpha. The most dramatic effects on ET1 levels were seen in rabbits treated with valsartan, where levels were reduced to values close to those for sham-operated animals (96.85 vs. 86.45 pg/ml). Captopril treatment led to a statistically significant (p<0.01) reduction in ET1 levels compared with untreated animals, but the reduction was only about half that seen with AT1receptor blockade. TXB2 levels doubled (202.58 vs. 413.28 pg/ml) upon arterial injury in control animals but rose by only 20—35% in rabbits treated with captopril (246.45 pg/ml) or valsartan (268.13). In untreated animals, 6-keto-PGF1-alpha levels decreased slightly after injury, but for both the captopril and valsartan groups, there were significant increases in levels of this prostaglandin derivative, effects attributed to the action of bradykinins. Levels were highest in the captopril-treated animals. Valsartan and captopril treatment led to a significant reduction in neointimal thickness and the extent of lumen stenosis compared with untreated animals. Both treatments were effective in reducing neointimal area and significantly (p<0.05) reduced cell proliferation. The differences between treatments can be attributed to the different actions of the agents, as valsartan leaves the AT2-receptor unblocked, while captopril, through inhibition of Ang II synthesis, prevents stimulation of both receptors. A combination of both treatments may be a possible way forward in the clinical prevention of restenosis.
Comparative antihypertensive and renoprotective effects of telmisartan and lisinopril after long-term treatment in hypertensive diabetic rats
Authors: Wienen Wolfgang , Richard Serge , Champeroux Pascal , Audeval-Gerard Chantal
Published: May 2007

This study compared the cardiovascular and renal effects of long-term telmisartan (3 and 10 mg/kg/day) and lisinopril (10 mg/kg/day) in an animal model combining hypertension and diabetes mellitus.

It was a parallel-group study of diabetic, spontaneously hypertensive rats (SHR), treated with control or active treatment for eight months. A non-diabetic SHR control group was run in parallel. Diabetes was induced by streptozotocin (45 mg/kg i.v.) in SHRs aged 9—10 weeks. Animals were treated with telmisartan (3 or 10 mg/kg/day), lisinopril (10 mg/kg/day) or vehicle. Plasma glucose levels, blood pressure (BP), and urinary protein and albumin excretion were measured monthly. Telmisartan treatment significantly reduced BP of diabetic SHRs in a dose-dependent manner (p<0.05, low-dose, n=18; p<0.01, high-dose, n=15). The BP reduction in the lisinopril group was similar to that in the telmisartan 10 mg/kg/day group. Compared with non-diabetic SHRs, untreated diabetic SHRs developed severe proteinuria and albuminuria over the experimental period (p<0.01). In diabetic SHRs, proteinuria and albuminuria were dose-dependently and significantly attenuated by treatment with telmisartan (p<0.01 with the higher dose) and lisinopril (p<0.01). Compared with the untreated diabetic SHRs, cardiac hypertrophy was significantly reduced after treatment with both doses of telmisartan and with lisinopril. Telmisartan, 10 mg/kg/ day, but not lisinopril, significantly attenuated the diabetes-induced increase in glomerular volume. In conclusion, telmisartan, 10 mg/kg/day, is at least as beneficial as lisinopril, 10 mg/kg/day, in lowering BP, reducing cardiac hypertrophy and attenuating renal excretion of protein and albumin in this model.
Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity
Authors: Petrescu Gheorghe , Costuleanu Marcel , Slatineanu Simona Mihaela , Costuleanu Natalia , Foia Liliana , Costuleanu Angela
Published: May 2007

It has been suggested that tyrosine kinase activity participates in the regulation of signal transduction associated with angiotensin II (Ang II)-induced pharmaco-mechanical coupling in rat aortic smooth muscle. We further tested the effects of genistein, a tyrosine-kinase inhibitor, and its inactive analogue, daidzein, on angiotensin I (Ang I), angiotensin III (Ang III) and angiotensin IV (Ang IV) contractions, as compared with those on Ang II. Genistein partially inhibited Ang II- and Ang I-induced contractions. The genistein-induced inhibition was more evident on Ang III and especially important on Ang IV contractile effects. Thus, Ang IV- and Ang III-induced contractions seem to be more dependent on tyrosine kinase activity than those evoked by Ang II or Ang I. Daidzein did not significantly affect the contractile effects of any of angiotensin peptides tested. These results clearly suggest that the inhibition of the action of angiotensin peptides actions by genistein is mediated by inhibition of endogenous tyrosine kinase activity. Furthermore, our data show that the type and/or intensity of tyrosine kinase activity is differentially associated with the contractile effects of different angiotensin peptides in rat aorta. Nifedipine, a blocker of membrane L-type Ca2+channels, strongly inhibited Ang IV-induced contractions. At the same time, it significantly inhibited Ang III contractile effects as compared with Ang II and Ang I contractions. Meanwhile, we observed a close relationship between calcium influx and tyrosine kinase phosphorylation activity under the stimulatory effects of angiotensin peptides. Furthermore, genistein did not significantly influence the phasic contractions induced by angiotensin peptides in Ca2+-free Krebs-Henseleit solution. Thus, it appears that Ca2+influx, rather than the release of Ca2+from IP3-sensitive stores, may play a major role in the contractile effects of angiotensin peptides in rat aorta via tyrosine kinase activation. One argument against a direct action of genistein on the Ca2+channel itself is that it did not markedly affect the K+-induced contraction (depolarisation) in rat aorta. At the same time, a potential role for tyrosine kinase activity in the process of calcium entry is suggested. An elevation of intracellular calcium via tyrosine kinase-mediated processes may mediate the actions of G-protein coupled receptor agonists in smooth muscle, including angiotensin peptides.
The effects of candesartan on vascular responses to angiotensin II and norepinephrine in normal volunteers
Authors: Tran Diane , Phoon Stephen , Howes Laurence
Published: May 2007

The effects of chronic administration of candesartan, 16 mg once-daily, to normal volunteers on cardiovascular responses to angiotensin II (Ang II) and norepinephrine (NE) were examined.

Fifteen healthy, non-smoking volunteers participated in a randomised, double-blind crossover study of two weeks of candesartan therapy, compared with two weeks of placebo. Blood pressure (BP) responses were measured to increasing infusion rates of intravenous Ang II and NE, along with forearm blood flow (FBF) responses into intra-brachial arterial Ang II, 2 and 24 hours after the last dose of candesartan or placebo. FBF responses to intra-brachial arterial NE were recorded approximately 2 hours following the final dose.

Systolic and diastolic BP responses to intravenous infusions of Ang II during candesartan treatment were completely suppressed and significantly lower than during placebo treatment, 2 hours (candesartan 96±10/55±8 mmHg; placebo 105±5/64±8 mmHg) and 24 hours (candesartan 94±8/54±8 mmHg; placebo 103±7/64±7 mmHg) following the last dose. In contrast, FBF responses to intra-brachial arterial Ang II were significantly suppressed by candesartan compared with placebo in a subgroup of subjects 2 hours following the last dose (n=9), but not 24 hours after the last dose (n=8). FBF responses to NE were also suppressed by candesartan treatment 2 hours following the last dose, while BP responses to intravenous NE were unaltered. Chronic candesartan therapy, 16 mg once-daily effectively suppresses pressor responses to Ang II over the duration of the dosing interval.
Pharmacological properties of angiotensin II antagonists: Examining all the therapeutic implications
Authors: Unger Thomas
Published: May 2007

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I), or more recently the Ang II AT1-receptor blockers (ARBs), has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.
High serum enalaprilat in chronic renal failure
Authors: Elung-Jensen Thomas , Heisterberg Jens , Kamper Anne-Lise , Sonne Jesper , Strandgaard Svend , Larsen Niels Erik
Published: May 2007

Background

Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.

Methods

Fifty nine out-patients with plasma creatinine >150 µmol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.

Results

Median glomerular filtration rate (GFR) was 23 (range 6—60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5—20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5—584.7) ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10—42) ml/minute/1.73 m 2. The median clearance of enalaprilat was 28 (16—68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.

Conclusion

Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.
Role of endothelin in cardiovascular disease
Authors: Agapitov Alexei V , Haynes William G
Published: May 2007

Endothelins are a family of peptides, which comprises endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), each containing 21 amino-acids. ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. ET-1 also has inotropic, chemotactic and mitogenic properties. In addition, it influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide and stimulates the sympathetic nervous system.

The overall action of endothelin is to increase blood pressure and vascular tone. Therefore, endothelin antagonists may play an important role in the treatment of cardiac, vascular and renal diseases associated with regional or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure and chronic renal failure. Long-term anti-endothelin therapy may improve symptoms and favourably alter the progression of heart failure.

Endothelin appears to participate in induction and progression of sclerotic renal changes, leading to progression to end-stage renal disease. Anti-endothelin therapy might offer additional benefits in the prevention of progression of chronic renal failure in addition to the known benefits of RAAS inhibition.

Clinical trials have demonstrated potentially important benefits of endothelin antagonists for patients with essential hypertension, pulmonary hypertension and heart failure. Further studies are necessary to determine the role of anti-endothelin therapy in the treatment of cardiovascular diseases and determine the different roles of selective receptor antagonism vs. mixed ETA/B-receptor antagonism in human diseases.
Comparative effects of cilazapril, carvedilol and their combination in preventing from left ventricular remodelling after acute myocardial infarction in rats
Authors: Yuejin Yang  , Yida Tang  , Yingmao Ruan  , Yongli Li  , Yanwen Zhou  , Runlin Gao  , Jilin Chen  , Zaijia Chen
Published: May 2007

Objectives

To compare the effects of cilazapril, carvedilol and their combination in preventing left ventricular remodelling (LVRM) after acute myocardial infarction (AMI) in rats.

Methods

Twenty-four hours after left coronary artery ligation, 100 surviving AMI female Sprague-Dawley rats were randomly assigned to: (1) AMI control (n=25); (2) cilazapril (Cila, 1 mg/kg/day) (n=25); (3) carvedilol (Car, 1 mg/kg/day) (n=25), and (4) cilazapril (1 mg/kg/day)+ carvedilol (1 mg/kg/day) (combination) (n=25) groups. A sham-operated group (n=17) was selected randomly as a non-infarction control. After four weeks of therapy with the drugs given by gastric gavage, haemodynamic studies were performed, following which the rat hearts were fixed and pathologically analysed. Rats with MI size <35% or >55% were excluded. Complete data were obtained in 64 rats, comprising AMI control (n=13), Cila (n=12), Car (n=12), Combination (n=14), and sham-operated (n=13) groups.

Results

There were no significant differences in MI size between the four AMI groups (45.2—46.7%, p>0.05). Compared with the sham-operated group, left ventricular (LV) end diastolic pressure (LVEDP), volume (LVV), weight (LVW), septal thickness (STh) and right ventricular weight (RVW) were all significantly increased (all p<0.001) in the AMI group, while the LV pressure maximal rate of rise and fall (±dp/dt) was significantly decreased (all p<0.001). In comparison with the AMI group, LVEDP, LVV, LVW, STh and RVW were all significantly decreased, while ±dp/dt was significantly increased in the Cila, Car, and combination groups, with LVEDP and STh decreasing more in the combination group than in the two monotherapy groups (p<0.05—0.01). There were no significant differences in other variables between the three therapy groups.

Conclusions

Cilazapril, carvedilol and their combination are all effective in preventing LVRM after AMI in rats, and in improving haemodynamics and LV function, with the combination therapy being superior to monotherapy in all respects.
Review: The frequent need for three or more drugs to treat essential hypertension. What evidence for optimal combinations?
Authors: Swift Pauline A , MacGregor Graham A
Published: May 2007

Treatment of high blood pressure (BP) reduces the risk of death and morbidity from stroke and coronary heart disease. There is accumulating evidence from large outcome studies that support a move towards lower treatment targets in hypertensives, particularly for those with concomitant risk factors or evidence of established target organ damage. At present, the achieved rates for BP control in the UK are very poor. Amongst the many possible reasons for poor BP control is the under utilisation of effective drug combinations. This article addresses the rationale for two and three drug combination therapy in hypertension and reviews the trial evidence for efficacy of combinations.
Review: Combining renin-angiotensin-aldosterone system blockade with diuretic therapy for treatment of hypertension
Authors: Motwani Joseph G
Published: May 2007

The rationale for using angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) in combination with thiazide diuretic therapy has centred formerly around antihypertensive synergy and counter-balancing adverse metabolic effects, particularly on potassium homeostasis. However, two recent landmark clinical trials that included high-risk hypertensive patients have now provided an evidence base for this form of combination therapy by demonstrating the efficacy of perindopril/indapamide and losartan/ hydrochlorothiazide in reducing vascular morbidity and mortality, a proportion of the benefit being unaccounted for by blood pressure reduction alone. Several unresolved issues remain concerning class effects versus specific drug effects, optimal dosing, potential differences in efficacy between ACE-I and ARBs, whether elderly mild hypertensives benefit from this form of combination therapy, and the possibility that the optimal regimen may be a triple combination of ACE-I, ARB and thiazide diuretic. These issues will be resolved by ongoing and future major endpoint trials in hypertension.
Regression of left ventricular hypertrophy: hoping for a longer life
Authors: Sharp Andrew , Mayet Jamil
Published: May 2007

Left ventricular hypertrophy (LVH) is more than just an adaptive response to hypertension. It predicts a poor prognosis independently of the blood pressure (BP) level. There is increasing evidence from studies such as Heart Outcomes Prevention Evaluation (HOPE) and Losartan Intervention For Endpoint reduction in hypertension (LIFE) that LVH should be a target for treatment, above and beyond BP control. It is likely that drugs blocking the renin-angiotensin-aldosterone system cause greater regression of LVH than other agents and this is probably the mechanism that explains the superiority of losartan over atenolol in the LIFE study. In order to achieve the stringent BP goals suggested by modern guidelines, most patients will require multiple antihypertensive agents and the clinical choices relate more often to which combinations of drugs are most appropriate, rather than which single drug is the best. Tight BP control should be the first priority and this is likely to lead to regression of LVH.
Effects of telmisartan on arterial stiffness in Type 2 diabetes patients with essential hypertension
Authors: Asmar Roland , Gosse Phillipe , Topouchian Jirar , N'tela Gilbert , Dudley Amanda , Shepherd Gillian L
Published: May 2007

Arterial wall stiffness, an important independent risk factor for cardiovascular disease in patients with hypertension, is worsened by the coexistence of diabetes mellitus. This randomised, prospective, double-blind, crossover trial assessed the effects of telmisartan on arterial stiffness in patients with Type 2 diabetes with essential hypertension. After a two-week placebo wash out period, 28 ambulatory patients received telmisartan (40 mg) or placebo for three weeks. Following a second two-week placebo wash out period, patients received the alternate treatment for a further three weeks. Augmentation index and central blood pressure (BP) were determined using the SphygmoCor™ device and pulse wave velocity (PWV) was measured using an automatic device, the Complior™, at the beginning and the end of each period. Telmisartan significantly reduced the carotid—femoral PWV compared with placebo (mean adjusted treatment difference —0.95 m/s; 95% CI: —1.67, —0.23 m/s; p=0.013). Peripheral and central diastolic, systolic and pulse pressures were also significantly reduced with telmisartan compared with placebo. In conclusion, telmisartan reduces arterial stiffness and peripheral and central BPs as assessed by PWV and pulse contour analysis in hypertensive patients with Type 2 diabetes. These properties of telmisartan suggest that it may improve cardiovascular outcome in this patient population.
ACE-I and ARBs in early diabetic nephropathy
Authors: Mauer Michael , Zinman Bernard , Gardiner Robert , Drummond Keith N , Suissa Samy , Donnelly Sandra M , Strand Trudy D , Kramer Michael S , Klein Ronald , Sinaiko Alan R
Published: May 2007

Introduction

Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest progression towards end-stage renal disease. Studies using `hard' endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (Vv[Mes/glom]).

Methods

This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.

Results

One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.

Conclusions

Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.
Effects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease
Authors:   Pacific Study Group, Neal Bruce
Published: May 2007

Introduction

Among individuals with a history of myocardial infarction (MI), higher levels of blood pressure (BP) are associated with increased long-term risks of death from coronary heart disease. Treatment with a BPlowering regimen, based on omapatrilat may result in greater clinical benefits than treatment with a regimen based on a regular angiotensin-converting enzyme (ACE) inhibitor because of more favourable effects on the renin-angiotensin-aldosterone system.

Methods

Seven hundred and twenty-three clinically stable patients with a history of MI or unstable angina, and a mean entry BP of 134/77 mmHg, were randomised to six months treatment with omapatrilat 40 mg, omapatrilat 20 mg, or matching placebo.

Results

After six months, mean BP levels (systolic/diastolic) in the omapatrilat 40 mg group were reduced by 4.3/ 2.9 mmHg (95% confidence interval 1.3 to 7.2/1.2 to 4.6). Mean BP levels in the omapatrilat 20 mg group were reduced by 4.6/1.0 mmHg (1.6 to 7.6/—0.7 to 2.6) in comparison with the placebo group. Both doses of omapatrilat also produced significant decreases in plasma ACE activity and significant increases in levels of plasma renin activity, atrial natriuretic peptide, endothelin and homocysteine (p<0.05 for all). Premature discontinuations were more frequent with omapatrilat than with placebo (p<0.001 for 20 mg and 40 mg).

Conclusions

Omapatrilat produced changes in BP, neurohormone and biochemical parameters that were similar for the two doses. The long-term clinical implications of the observed effects are uncertain and a large-scale randomised trial would be required to reliably establish the effects of omapatrilat on the risks of major vascular disease events among patients with coronary heart disease.
Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats
Authors: Deelman Leo E , Navis Gerjan , de Boer Erik , Wietses Mirian , de Zeeuw Dick , Henning Robert H
Published: May 2007

Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney.

Unilateral adriamycin-induced proteinuria was obtained by clamping the left renal artery before injection of adriamycin. In control animals, both left and right renal arteries were clamped. Twelve weeks later, mRNA expression of RAS components was determined in both kidneys. In the affected and non-affected kidney of the unilateral proteinuric rat, we demonstrate up-regulation of angiotensin-converting enzyme (ACE) mRNA (213%±22 and 188%±24 of controls, respectively), up-regulation of transforming growth factor (TGF- ) mRNA (956%±229 and 418%±56) and down-regulation of angiotensin type 2 receptor (AT2-R) mRNA (24%±5 and 20%±5). The expression of angiotensin type 1 receptor (AT1-R) mRNA and inositol 1,4,5-trisphosphate receptor type I (IP3R-I) mRNA were unchanged.

In conclusion, renal expression of ACE, AT2-R, and AT1-R mRNA is not mediated by protein leakage. Local intrarenal protein leakage did influence renal TGF- mRNA expression.
Involvement of renal ACE activity in proteinuria-associated renal damage in untreated and treated adriamycin nephrotic rats
Authors: Bos Hendrik , Laverman Gozewijn D , Henning Robert H , Tiebosch Anton TMG , de Jong Paul E , de Zeeuw Dick , Navis Gerjan
Published: May 2007

Proteinuria is assumed to play a pathogenetic role in progressive renal damage. Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria and provides renoprotection. This suggests that ACE activity might play a pathogenetic role in the development of proteinuria-induced renal structural damage. We investigated this hypothesis in untreated and treated established adriamycin nephrosis, a model of proteinuria-induced renal damage.

In a time-course experiment, the development of renal structural damage in untreated adriamycin nephrotic rats was paralleled by a significant rise in renal ACE activity. Moreover, on cross-sectional analysis, a consistent positive correlation between renal, but not plasma, ACE activity and proteinuria, focal glomerulosclerosis and interstitial injury was present. Notably, these associations were present, not only in the untreated condition, but also during intervention with either ACE inhibition or AT1-receptor antagonism. Interestingly, we found that higher renal ACE activity is associated with more severe renal damage for a given amount of proteinuria, suggesting that renal ACE activity may be either a permissive or a promoting factor in the processes by which proteinuria eventually leads to renal structural damage. This relationship was abolished by renin-angiotensin system (RAS)-blockade, suggesting that RAS-mediated effects are involved in the relationship between renal ACE activity and proteinuria-induced renal damage.

In conclusion, in untreated as well as treated adriamycin nephrotic rats, renal ACE activity is closely associated with renal outcome. This association appears to be independent of the specific mode of blockade of the RAS. Renal ACE activity is a consistent marker of individual differences in proteinuria-associated renal damage: further studies are needed to investigate a possible pathogenetic role in renal damage.
Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure
Authors: Chee Kok H , Amudha Kadirvelu , Hussain Nik A , Haizal Haron K , Choy Anna-Maria J , Lang Chim C
Published: May 2007

Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.
Ramipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction
Authors: Linz Wolfgang , Itter Gabi , Dobrucki Lawrence W , Malinski Tadeusz , Wiemer Gabriele
Published: May 2007

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI).

Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo- treated animals with CHF. Concomitantly, the increased CaI-stimulated O 2production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FUtreatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA.

Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.
Effects of ACE inhibition and AT1-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients
Authors: Yavuz Dilek , Koç Mehmet , Toprak Ahmet , Akpιnar Ihsan , Velioğlu Ayliz , Deyneli Oguzhan , Haklar Goncagül , Akalln Sema
Published: May 2007

Objective

Disturbed endothelial function is closely associated with hyperinsulinaemia and insulin resistance in essential hypertension. The aims of this study were:

1) to evaluate whether the two alternative drugs, angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II (Ang II) antagonists, had comparable effects on glucose metabolism and endothelial function.

2) to determine whether they improve endothelial dysfunction through modulating insulin resistance and oxidative stress.

Study design and methods

Study design and methods

Essential hypertensive patients were randomised into two groups: Twelve (nine patients in final analysis) patients were given enalapril (enalapril group), and twelve (nine patients in final analysis) were given losartan (losartan group). Twelve sex- and age-matched normotensive volunteers were included as controls. Before and after six months of treatment, endothelial function, insulin sensitivity and lipid peroxidation (TBARs) and NO metabolites (NOx) were evaluated.

Results

Endothelial function, measured as flow mediated dilatation (FMD), was improved in both of the treatment groups (p=0.0001). Calculated insulin sensitivity index also improved in the enalapril-treated group (p=0.05) but not in the losartan-treated group, compared with baseline levels. TBARS values decreased significantly in the enalapril group compared with baseline levels (p<0.001). FMD was positively correlated with insulin sensitivity index (r=0.32, p<0.05) and NOx levels (r=0.39, p=0.01) and negatively correlated with TBARS levels (r=-0.53, p=0.0002) in hypertensive patients.

Conclusion

Inhibition of the renin-angiotensin system, either with ACE inhibitors or AT1-receptor blockers improves endothelial dysfunction. ACE inhibition has prominent effects on improving insulin sensitivity and decreasing oxidative stress in essential hypertensive patients.
Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility
Authors: Trongtorsak Petcharat , Morgan Trefor O , Delbridge Lea MD
Published: May 2007

Introduction Blockade of the renin-angiotensin system (RAS) by combined angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor (AT1) antagonist treatment with reduced dietary sodium intake produces suppression of cardiac growth and regression of cardiac hypertrophy. The purpose of this study was to investigate whether cardiac growth suppression by combined RAS blockade under conditions of dietary sodium restriction is associated with cardiomyocyte atrophy and contractile dysfunction and whether this intervention modifies cardiomyocyte inotropic responsiveness to angiotensin II (Ang II).

Methods Rats were fed a high (4% w/w) or low (0.2% w/w) NaCl diet for six days. Both groups were then given a combined intraperitoneal injection of perindopril (6 mg/kg/day) and losartan (10 mg/kg/day) with maintained dietary treatment for another seven days. At the end of the treatment period, animals were anaesthetised and their hearts were removed and weighed. Left ventricular cardiomyocytes were isolated by enzymatic dissociation and cell dimensions were evaluated. A line scan camera and digital imaging technique were used to assess cardiomyocyte contraction and inotropic responses to exogenous Ang II (10-10to 10-8M).

Results Dietary treatment alone had no effect on body growth, whereas combined RAS blockade suppressed somatic growth in the low sodium (LS) group, compared with the high sodium (HS) group. This growth suppression in the LS group was also evident in the heart at the organ and cellular level. Studies of cardiomyocyte contraction showed that myocytes from the LS group exhibited contractile instability and depression of contractile performance. Compared with the HS group, myocytes from the LS group showed a significant reduction in maximum cell shortening (6.40±0.17 vs. 7.32±0.16% resting length, p<0.05), and maximum rate of shortening (3.85±0.14 vs. 4.29±0.11 cell length/ms, p<0.05). Myocytes of the HS group exhibited negative inotropic responses to Ang II at all concentrations tested, with a significant reduction in maximum cell shortening by 11—16% after 12 minutes peptide exposure (p<0.05 vs. non-treated control). In comparison, Ang II elicited both positive and negative responses in myocytes from the LS group, with a predominant negative inotropic effect.

Conclusions This study provides evidence that combined RAS blockade treatment under restricted sodium intake conditions can impair cardiomyocyte contractile function in association with cardiomyocyte growth suppression. Chronic RAS blockade qualitatively alters the intrinsic inotropic status and responsiveness of ventricular cardiomyocytes, and this shift is further modulated by dietary sodium intake conditions.
Telmisartan Effectiveness on Left ventricular MAss Reduction (TELMAR) as assessed by magnetic resonance imaging in patients with mild-to-moderate hypertension — a prospective, randomised, double-blind comparison of telmisartan with metoprolol over a period of six months — rationale and study design
Authors: Friedrich Matthias G , Dahlöf Björn , Sechtem Udo , Unger Thomas , Knecht Mathias , Dietz Rainer , TELMAR Investigators
Published: May 2007

The Telmisartan Effectiveness on Left ventricular MAss Reduction (TELMAR) trial will assess the effect of the angiotensin II (Ang II) receptor blocker, telmisartan, on left ventricular hypertrophy (LVH) compared with the β-blocker, metoprolol, at similar antihypertensive doses. The rationale is that antihypertensives reduce LVH, a cardiac adaptation to pressure overload, principally by pressure-related effects. Ang II plays a key role in pressure-independent mechanisms causing LVH, and angiotensin-converting enzyme (ACE) inhibitors induce more pronounced LVH regression than some other antihypertensives. Blocking Ang II Type 1 receptors may be more effective than ACE inhibition in reducing LVH. TELMAR is a prospective, randomised, double-blind, double-dummy, parallel-group trial. A total of 140 patients (age 18—80 years) with uncontrolled essential hypertension (mean daytime systolic blood pressure [SBP] ≥140 mmHg or diastolic blood pressure [DBP] ≥90 mmHg and night-time SBP ≥120 mmHg or DBP ≥70 mmHg, measured by ambulatory blood pressure monitoring [ABPM]) and left ventricular mass index related to height (LVMI) >0.8 g/cm for females, >1.1 g/cm for males (defined by magnetic resonance imaging [MRI]) will be randomised to once-daily telmisartan or metoprolol. The telmisartan dose will be 40 mg for the first two weeks, 80 mg for 5.5 months and 40 mg for the last two weeks. Metoprolol will be given at a dose of 47.5 mg for two weeks, 95 mg for 5.5 months and 47.5 mg for two weeks. Concomitant add-on medication with hydrochlorothiazide and amlodipine will be allowed. The primary endpoint is the percentage change in LVMI at treatment end versus baseline, using MRI. Secondary variables include blood pressure changes and response rates assessed by ABPM and manual cuff sphygmomanometry, and end-systolic wall stress, systolic left ventricular function (LVF) and diastolic LVF determined by MRI. A separate study was performed prior to the main trial to define the normal range of MRI data in an age-matched population.