Candesartan Cilexetil Treatment Research Articles

Candesartan cilexetil ameliorates NOSTRIN-NO dependent portal hypertension in cirrhosis and ACLF

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the “angiotensin II type 1 receptor blocker” candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.

Nephroprotective effects of Candesartan Cilexetil against Cyclosporine A-induced nephrotoxicity in a rat model.

Cyclosporine A (CsA), a well-known immunosuppressive drug, has been prescribed after organ transplantation and in a variety of disorders with an immunological origin. Nephrotoxicity is one of the most frequently stated problems associated with CsA, and therefore the treatment with CsA remains a big challenge. This study sets out to assess the ameliorative influences of Candesartan Cilexetil (CC) on oxidative stress and the nephrotoxic effect of CsA in a rat model. Twenty-four Wister Albino rats, 7-8-week-old, weighing 150-250g, were randomly categorized into three groups (eight animals in each group). These groups were the (1) CsA-treated group, (2) vehicle-treated group, and (3) CC-treated group. Bodyweights were assessed at the start and end of experiments. Renal function test and levels of glutathione peroxidase 1 catalase -CAT (Gpx1), catalase (CAT), superoxide dismutase (SOD), interleukin -2 (IL-2), and malondialdehyde (MDA) were investigated in renal tissues. Histological changes in kidneys were also evaluated. Data showed that levels of urea and creatinine in serum and levels of IL-2 and MDA in renal tissues were elevated in the CsA-treated group, with severe histological changes compared with the control group. Furthermore, tissue levels of Gpx1, CAT, and SOD were significantly decreased in CsA-treated in comparison with the control group. Treatment with CC for the rats subjected to CSA resulted in a marked reduction in levels of serum urea and creatinine and tissue levels of IL-2 and MDA. Levels of Gpx1, CAT, and SOD in renal tissues were greater in the CC-treatment group compared with the CsA-treated group. CC treatment reduced the deterioration of renal morphology compared with CsA treatment. The findings of this study suggest that CC could prevent CSA-induced nephrotoxicity through its anti-inflammatory and antioxidant influences. Considerably more work needs to be done to determine the mechanistic insight behind the ameliorative effect of CC.

Candesartan Cilexetil Attenuates Arrhythmogenicity Following Pressure Overload in Rats via the Modulation of Cardiac Electrical and Structural Remodeling and Calcium Handling Dysfunction.

BackgroundCardiac hypertrophy is associated with abnormal electrophysiology and increased arrhythmia risk. This study assessed whether candesartan cilexetil, an angiotensin II type 1 receptor blocker, could suppress arrhythmogenecity by attenuating cardiac electrical remodeling and calcium mishandling in rats with pressure‐overload hypertrophy.Methods and ResultsMale Sprague‐Dawley rats were randomly subjected to abdominal aorta banding or sham procedure and received either candesartan cilexetil (3.0 mg/kg per day) or vehicle by gavage for 5 weeks. Pressure overload was characterized by compensated left ventricular (LV) hypertrophy and fibrosis, increased LV pressure and its decay time, and prolonged corrected QT interval, all of which were attenuated by candesartan cilexetil treatment. Candesartan cilexetil–treated banded rat hearts displayed shorter QT intervals and lower vulnerability to atrial and ventricular tachyarrhythmias than vehicle‐treated banded hearts. Candesartan cilexetil prevented banding‐induced prolonged action potential duration and reduced the occurrence of triggered activity in LV papillary muscles. In addition, the prolonged time to 50% cell relengthening and calcium transient decay time were normalized in LV myocytes from candesartan cilexetil–treated banded rats, along with a normalization of decreased SERCA2a (sarco[endo]plasmic reticulum calcium‐ATPase) expression in LV tissues. Furthermore, candesartan cilexetil normalized depressed transient outward potassium current densities and protein and mRNA levels of both voltage‐gated potassium 4.2 and 4.3 channel subunits (Kv4.2 and Kv4.3) in banded rats.ConclusionsCandesartan cilexetil protects the heart from pressure overload‐induced adverse electrical remodeling by preserving potassium channel densities. In addition, calcium handling and its molecular regulation also improved after treatment. These beneficial effects may contribute to a lower susceptibility to arrhythmias in hearts from candesartan cilexetil–treated pressure‐overloaded rats.

Candesartan cilexetil prevents diet-induced insulin resistance via peroxisome proliferator-activated receptor-γ activation in an obese rat model.

Angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been shown to reduce the incidence of type 2 diabetes mellitus; however, the underlying molecular mechanism is unknown. Peroxisome proliferator-activated receptor γ (PPARγ) is the central regulator of insulin and glucose metabolism, which improves insulin sensitivity. Whether candesartan cilexetil, as a prodrug of the AT1R blocker candesartan, has PPARγ-activating properties remains to be elucidated. The aim of the present study was to investigate the effects of oral administration of candesartan cilexetil on glucose tolerance and the actions of PPARγ on liver and adipose tissue in the insulin-resistant obese rat induced by high-fat diet. Animals treated with candesartan cilexetil showed an improved glucose tolerance after oral glucose challenge. Whole-body insulin sensitivity was evaluated using the hyperinsulinemic-euglycemic clamp technique. During high-fat feeding in high-fat diet (HF) rats, the glucose infusion rate (GIR) was 52.3% lower than that in normal chow (NC) rats. However, the GIR was significantly enhanced following candesartan cilexetil treatment. Angiotensin II receptor antagonism also resulted in significant increases in PPARγ protein expression in adipose and liver tissue. These results indicate that PPARγ activation by candesartan cilexetil may provide novel therapeutic options in the treatment of patients with metabolic syndrome.

Candesartan Cilexetil in Children and Adolescents Aged 1 to &lt;17 Years with Hypertension†

Candesartan cilexetil is the orally administered prodrug of candesartan, an angiotensin II subtype 1 receptor antagonist. The pharmacokinetics (area under the plasma concentration-time curve and maximum plasma concentration) of candesartan do not appear to be affected by age, sex, or weight, with a similar exposure observed in children aged 1 to 6 years and adults. Therapy with candesartan cilexetil 0.05, 0.20, and 0.40 mg/kg/day for 4 weeks was effective in the treatment of hypertension in children aged 1 to <6 years, inducing significant dose-dependent reductions from baseline in sitting SBP (SSBP) [primary endpoint] and sitting DBP (SDBP) in the double-blind phase of a randomized, parallel-group, multinational, dose-ranging clinical study. The criteria for antihypertensive response (SBP and DBP values that were less than the 95th percentile) were met by 28-66% of patients. The beneficial antihypertensive effects of candesartan cilexetil therapy were sustained for up to 160 weeks. No significant difference from zero in the slope of the placebo-adjusted change in SSBP (primary endpoint) and SDBP was observed across the three candesartan cilexetil treatment groups (candesartan cilexetil 2, 8, or 16 mg/day in patients weighing <50 kg and candesartan cilexetil 4, 16, or 32 mg/day in patients weighing ≥50 kg) during the double-blind phase of a randomized, double-blind, parallel-group, placebo-controlled, multinational, dose-ranging study in children and adolescents aged 6 to <17 years. Nonetheless, candesartan cilexetil demonstrated significantly greater changes from baseline to the end of the double-blind phase than placebo in SSBP and SDBP, with a significantly higher proportion of patients receiving candesartan cilexetil meeting the criteria for antihypertensive response than those receiving placebo. Antihypertensive response rates were sustained for 52 weeks. Candesartan cilexetil therapy for up to 160 weeks was generally well tolerated in clinical studies in children and adolescents aged 1 to <17 years with hypertension.

Effects of angiotensin II AT1 receptor inhibition and exercise training on insulin action in rats on high-fat diet

AimThis study was to determine whether combination of the angiotensin II AT1 receptor blocker (ARB), candesartan cilexetil, and exercise training can prevent the development of high-fat diet-induced insulin resistance. Main methodsF344/NSlc rats were fed normal chow diet or high-fat (HF) diet for 7weeks. The HF-fed rats were either administered candesartan cilexetil (5mg·kg−1·day−1), exercise-trained, or received a combination of these 2 treatments. Key findingsOral glucose tolerance tests (OGTT) showed that combined treatment with candesartan cilexetil and exercise increased glucose tolerance as compared with each treatment alone in HF-fed rats. Moreover, euglycemic–hyperinsulinemic clamp analysis showed improvement in glucose infusion rate with exercise training or candesartan cilexetil treatment alone, and further improvement was observed with the combination treatment. Systolic blood pressure improved with candesartan cilexetil but not with exercise alone. Finally, Glut-4 protein expression in soleus muscle was decreased with HF diet, and the expression was increased by exercise and not candesartan cilexetil treatment. SignificanceThese results suggest that the combination of candesartan cilexetil and exercise training improves insulin resistance as compared with each treatment alone.

Candesartan Cilexetil

Candesartan cilexetil is the orally administered prodrug of candesartan, an angiotensin II subtype 1 receptor antagonist. The pharmacokinetics (area under the plasma concentration-time curve and maximum plasma concentration) of candesartan do not appear to be affected by age, sex, or weight, with a similar exposure observed in children aged 1 to <6 years or >6 years and adults. Therapy with candesartan cilexetil 0.05, 0.20, and 0.40 mg/kg/day for 4 weeks was effective in the treatment of hypertension in children aged 1 to <6 years, inducing significant dose-dependent reductions from baseline in sitting SBP (SSBP) [primary endpoint] and sitting DBP (SDBP) in the double-blind phase of a randomized, parallel-group, multinational, dose-ranging clinical study. The criteria for antihypertensive response (SBP and DBP values that were less than the 95th percentile) were met by 28-66% of patients. The beneficial antihypertensive effects of candesartan cilexetil therapy were sustained for up to 160 weeks. No significant difference from zero in the slope of the placebo-adjusted change in SSBP (primary endpoint) and SDBP was observed across the three candesartan cilexetil treatment groups (candesartan cilexetil 2, 8, or 16 mg/day in patients weighing <50 kg and candesartan cilexetil 4, 16, or 32 mg/day in patients weighing ≥50 kg) during the double-blind phase of a randomized, double-blind, parallel-group, placebo-controlled, multinational, dose-ranging study in children and adolescents aged 6 to <17 years. Nonetheless, candesartan cilexetil demonstrated significantly greater changes from baseline to the end of the double-blind phase than placebo in SSBP and SDBP, with a significantly higher proportion of patients receiving candesartan cilexetil meeting the criteria for antihypertensive response than those receiving placebo. Antihypertensive response rates were sustained for 52 weeks. Candesartan cilexetil therapy for up to 160 weeks was generally well tolerated in clinical studies in children and adolescents aged 1 to <17 years with hypertension.

Pharmacokinetics and Antihypertensive Effects of Candesartan Cilexetil in Patients Undergoing Haemodialysis

In patients with endstage renal failure (ERF), activation of the renin-angiotensin-aldosterone system plays an important role in the onset and maintenance of arterial hypertension. This study aimed to elucidate the antihypertensive effect, pharmacokinetics and safety of candesartan cilexetil in patients with ERF undergoing haemodialysis. In 14 anuric hypertensive patients undergoing haemodialysis (mean+/- SD 24-hour systolic [SBP]/diastolic [DBP] blood pressure [BP] 142.9 +/- 11.1/75.0 +/- 10.1 mmHg), 24-hour BP measurements on the second interdialysis day per week were performed at baseline and at weeks 4, 12 and 24. All patients started antihypertensive treatment with candesartan cilexetil 4 mg once daily immediately before the start of haemodialysis. Subsequently, the dose was titrated upward to 8 mg once daily until the patient's mean ambulatory BP measurement (ABPM) values were <130/80 mmHg. Plasma candesartan pharmacokinetics were investigated on days 7 and 14 after starting candesartan cilexetil treatment and after each titration step. After 6 months all patients demonstrated well controlled BP (ABPM mean +/- SD SBP 129.6 +/- 21.7/DBP 69.4 +/- 10.4 mmHg) and a significantly reduced pulse pressure (from a mean +/- SD 67.9 +/- 13.7 mmHg at baseline to a mean +/- SD 60.2 +/- 14.7 mmHg at 6 months), without any adverse events. Candesartan plasma concentrations increased over 3 hours followed by a continuous decline. Plasma concentrations remained stable after 7 and 14 days, independent of dosing. However, administration of candesartan cilexetil 8 mg (five patients) resulted in plasma concentrations about 1.4 times higher than those for candesartan cilexetil 4 mg. In this study with small number of patients with ERF undergoing haemodialysis, candesartan cilexetil was effective in lowering BP and pulse pressure without accumulation or associated adverse effects such as elevated potassium or symptomatic hypotension.

I037 Impaired beta-adrenoceptor-mediated-vasorelaxation to celiprolol is improved by candesartan cilexetil treatment in spontaneously hypertensive rats

Celiprolol, a beta-blocker of third generation, is known to induce beta2-adrenoceptors (-AR) -mediated vasodilation, but the role of other beta-AR subtypes has not been investigated. Thus, the first purpose of this study was to evaluate the participation of beta3-AR in the celiprolol-induced relaxation in Wistar Kyoto rat (WKY) thoracic aorta. Furthermore, the second objective was designed to determine whether the celiprolol-induced relaxation was altered in spontaneously hypertensive rat (SHR) aorta, and to evaluate the effect of systemic or local angiotensin II (AngII) AT1 receptor (AT1R) antagonism on the relaxant effect of celiprolol. Aortic rings were mounted in organ baths and preconstricted with phenylephrine. Cumulative concentration response curves to celiprolol (0.1 to 300 μm) were established in different experimental conditions. Celiprolol produced a significant concentration dependent relaxation in WKY aorta (Emax=66.85±5.4 %, n=10) which was decreased in the presence of nadolol (beta1/beta2-AR antagonist, 10 μm) or SR59230A (beta3-AR antagonist, 1 μm). Relaxation to celiprolol was greatly decreased in denuded aortic rings, and abolished in intact rings pre-treated with L-Name (NOsynthases inhibitor, 100 μm). In SHR aorta, celiprolol-induced relaxation was significantly reduced (Emax=39.4±4.1 %, n=8) compared to WKY, whereas endothelium removal did not alter celiprolol-induced vasorelaxation. A 12 days treatment with candesartan cilexetil (AngII AT1R antagonist, 0.37 or 1 mg/kg/day) reduced systolic blood pressure (SBP) in both WKY and SHR, and significantly improved aorta relaxation to celiprolol more in SHR than in WKY (WKY : Emax=71.7±5,1 %, n=12 ; SHR : Emax=64.2±3.9 %, n=14). Furthermore, local aortic AT1R antagonism with candesartan CV11974 (100 mM) improved celiprolol-induced relaxation, but only in WKY aorta (Emax=78±5.6 %, n=7). Celiprolol induced an endothelial beta1-, beta2-and beta3-AR relaxation in WKY aorta through NO pathway. In SHR aorta, we showed, for the first time, that the celiprolol-induced vasorelaxation was impaired and that only the systemic AT1R antagonism with candesartan cilexetil improved the celiprolol-induced relaxation. This indicated that the beneficial effect of candesartan cilexetil was likely related to decreased SBP but not to specific mechanisms that may occur in aortic smooth muscle and/or endothelial cells.

Long-Term Angiotensin II Blockade May Improve Not Only Hyperglycemia but Also Age-Associated Cardiac Fibrosis

In the present study, the effects of long-term angiotensin (Ang) II antagonism on the development of cardiac and endothelial disorders were examined in Spontaneously Diabetic Torii (SDT) rats. Blood glucose concentration started to increase markedly in the untreated SDT rats from 20 weeks of age, while the blood glucose concentrations of candesartan cilexetil–treated SDT rats were significantly lower until 30 weeks of age. Cardiac function deteriorated in SDT rats and was accompanied by severe cardiac fibrosis, cardiac hypertrophy, and microstructural pathologic change in cardiomyocytes. Cardiac function was very well preserved in the age-matched Sprague Dawley (SD) rats, but cardiac fibrosis developed with aging. Candesartan cilexetil treatment improved cardiac structural remodeling and cardiac function in SDT rats. Surprisingly, the degree of cardiac fibrosis in candesartan cilexetil–treated SDT rats was less than that of SD rats. Immunohistological staining confirmed that in addition to collagen deposition, fibroblasts and myofibroblasts were the main cellular components in the cardiac fibrotic areas. The diabetic hearts showed positive staining for ACE, Ang II, and AT1 receptors. SDT rats also showed decreased endothelial function, which was improved with candesartan cilexetil treatment. These findings indicate that Ang II is involved in the development of cardiac dysfunction by accelerating cardiac remodeling and cardiomyocyte damage in the presence of hyperglycemia. On the other hand, although the mechanisms responsible for the cardiac fibrosis that occurs under normal conditions may differ greatly from those responsible for cardiac fibrosis with hyperglycemia, Ang II seems to play an important role in both.

Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation

Background To evaluate the effect of supraphysiological levels of angiotensin II and selective angiotensin II type 1 receptor (AT1-receptor) blockade on neointimal formation and systemic endothelial function after stent implantation in the rat abdominal aorta. Methods Male Wistar rats were randomized to one of three groups; control ( n = 8), angiotensin II infusion ( n = 9, 200 ng/kg/min), or candesartan cilexetil ( n = 8,AT1-receptor blocker; rats received 14.4 mg kg − 1 day − 1 ). Stents were implanted in the abdominal aorta. Histological analyses were performed at 4 weeks. Endothelial function was determined in isolated thoracic aortic rings. Results Neointimal area was increased in the angiotensin II treated group versus the control group, 0.88 mm 2 ± 0.21 versus 0.66 mm 2 ± 0.16 ( P < 0.05). Neointimal thickness was 171 μm ± 44 in angiotensin II treated animals and 120 μm ± 25 in the control group ( P < 0.05). In addition, endothelial function was attenuated in angiotensin II treated animals ( P = 0.01). Candesartan cilexetil treatment did not result in reduction of neointimal area and did not reduce neointimal thickness compared to the control group. Candesartan had no effect on endothelial function. Conclusions Supraphysiological levels of angiotensin II aggravates neointimal formation in the stented rat abdominal aorta, and in parallel decreases endothelial function. AT1-receptor blockade does not reduce neointimal formation in rats without supraphysiological angiotensin II levels.

Long-term angiotensin II AT 1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARγ

To clarify the mechanism of the effects of angiotensin II AT 1 receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT 1 receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFα) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, Candesartan cilexetil increased epididymal expression of PPARγ mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARγ activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT 2 receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT 1 receptor inhibition, angiotensin II AT 2 receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin–angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFα and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties.

Treatment with AT 1 receptor blocker restores diabetes-induced alterations in intracellular Ca 2+ transients and contractile function of rat myocardium

We investigated the effect of treatment with an angiotensin II receptor blocker, candesartan-cilexetil, on the mechanical and electrophysiological properties of cardiomyocytes isolated from streptozotocin-induced diabetic (STZ) rats. Contractile activity and electrophysiological properties were measured in papillary muscle and ventricular cardiomyocytes from normoglycemic and STZ-induced diabetic rats given vehicle or 5 mg/kg/day candesartan-cilexetil for 4 weeks. Alterations in the kinetics of contractile activity and intracellular Ca 2+ transients were observed as well as a typical prolongation of action potential duration and significant decrease of potassium currents in diabetic rat heart preparations. Candesartan-cilexetil treatment recovered significantly prolonged action potential and depressed potassium currents in diabetic rats. It was also shown that treatment with AT 1 blocker restored altered kinetics of both the Ca 2+ transients in cardiomyocytes and the contractile activity in papillary muscle strips of diabetic rats. We also showed that incubation of cardiomyocytes from diabetic rats with a protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM) had a similar effect to candesartan treatment on the Ca 2+ transients. Thus, angiotensin II receptor blockade protects the heart from the development of cellular alterations typically related with diabetes, and this action of AT 1 receptors seems to be related with the activity of PKC.

Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat: The effect of AT1-R blocker on the hepatic fibrosis

Angiotensin converting enzyme (ACE) and angiotensin II (AT-II) have been suggested to play an important role in liver fibrogenesis. There is a significant relationship between inheritance of hightened expression of transforming growth factor beta1 (TGF-beta1) and AT-II and the development of progressive hepatic fibrosis. The purpose of this study was to investigate the effects of captopril, an ACE inhibitor and candesartan cilexetil, an AT-II type 1 receptor (AT1-R) blocker, on liver fibrosis induced in rats by carbon tetrachloride (CCl4) administration. rats were divided into 4 experimental groups: The first group was given CCl4 alone; the second was given both CCl4 and captopril (100 mg x kg(-1) x day(-1)); the third was given both CCl4 and candesartan cilexetil (8 mg x kg(-1) x day(-1)); fourth group was given 0.9% NaCl only. Seven weeks after initiating the treatment, indices of fibrosis were assessed. Candesartan cilexetil treatment significantly reduced the fibrosis development. These inhibitory effects were not observed in the captopril-treated group. The mean fibrosis score was significantly lower in the CCl4/candesartan group compared with the group applied to CCl4 alone and the group applied to CCl4/captopril. Similarly, the number of alpha-smooth muscle actin positive cells was markedly suppressed by candesartan treatment. The results suggest that AT-II plays a pivotal role in hepatic fibrogenesis and candesartan significantly attenuates the progression of liver fibrosis. This drug may provide an effective new strategy for prevention of liver fibrosis. Its effectiveness should be investigated in chronic liver disease associated with progressive fibrosis.

Candesartan cilexetil: an update of its use in essential hypertension.

Candesartan cilexetil is converted to the angiotensin II receptor antagonist candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of candesartan to the angiotensin II type 1 (AT(1)) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic BP and diastolic BP are achieved with a once-daily dosage of candesartan cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, candesartan cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day candesartan cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, candesartan cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of candesartan cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with candesartan cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with candesartan cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with candesartan cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of candesartan cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity. Candesartan cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that candesartan cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, candesartan cilexetil is a useful therapeutic option in the management of patients with hypertension.

Influence of AT 1 Receptor Blockade on Blood Pressure, Renal Haemodynamics and Hormonal Responses to Intravenous Angiotensin II Infusion in Hypertensive Patients

The aim of this study was to investigate blood pressure, renal haemodynamics, hormone secretion and the responses to angiotensin II infusion during candesartan cilexetil (candesartan), losartan potassium (losartan) and valsartan treatment in patients with essential hypertension. In this double-blind, randomized, crossover study, 24 patients (mean blood pressure of 163/97 mmHg), received candesartan 16 mg, losartan 50 mg and valsartan 80 mg once daily (o.d.) for 4 weeks after a placebo run-in period. At the end of each period, angiotensin II (0.5, 1.0 and 1.5 ng/min/kg) was infused 24 h after the previous drug administration. Each dose of angiotensin II was infused for 45 min. Before infusion and at the end of each infusion step, blood pressure and renal haemodynamics were assessed and plasma renin activity and plasma concentrations of angiotensin II and aldosterone were measured. During treatment with candesartan, resting mean arterial pressure (mean - SEM, 106 - 2 mmHg) was significantly decreased compared with treatment with losartan (110 - 2 mmHg) and valsartan (109 - 2 mmHg). Candesartan inhibited the angiotensin II induced increase in filtration fraction (0.8 - 0.4%) significantly more than losartan (1.5 - 0.4%) and valsartan (1.6 - 0.4%) and reduced the increase in aldosterone secretion (17 - 5 pg/ml/) significantly more than losartan (74 - 17 pg/ml/) and valsartan (82 - 19 pg/ml/). In conclusion, candesartan 16 mg o.d. reduced resting blood pressure significantly more than losartan 50 mg o.d. and valsartan 80 mg o.d. Candesartan almost completely inhibited the exogenous angiotensin II induced renal vasoconstriction, effectively inhibited the increase in filtration fraction and significantly blunted aldosterone secretion compared with losartan and valsartan, indicating a more effective AT 1 receptor blockade with candesartan.

Candesartan prevents L-NAME-induced cardio-renal injury in spontaneously hypertensive rats beyond hypotensive effects.

Our goal was to assess the cardiovascular and renal protection afforded by angiotensin II type 1-receptor blockade against NG-nitro-L-arginine methyl ester (L-NAME)-exacerbated hypertension in young spontaneously hypertensive rats (SHR), in comparison with the antihypertensive drug, hydralazine. Male SHR were assigned to four groups (n=8 per group): no treatment (controls); L-NAME-treated group (20 mg/kg/day, 10 days, orally); co-treatment with L-NAME and hydralazine (15 mg/kg/day, by gavage); co-treatment with L-NAME and candesartan cilexetil (10 mg/kg/day, by gavage), i.e. at a dose that inhibited acute pressor responses to 5-20 ng angiotensin II. One animal died in the L-NAME group, and tail-cuff systolic blood pressure (SBP) increased significantly compared with controls to 201±5 mmHg. Albumin excretion increased 235-fold in L-NAME-treated rats. Heart weight index averaged 3.5±0.1 and 3.8±0.1 mg/g body weight (p<0.05) in control and L-NAME rats, respectively, indicating moderate cardiac hypertrophy induced by L-NAME. Preglomerular vascular lesions affected 63±6% of interlobular arteries and 10±2% of afferent arterioles (vs. 8±3 and 0.8±0.4% in controls, respectively). Hydralazine and candesartan cilexetil treatment similarly reduced SBP to 153±7, and 165±6 mmHg, respectively. However, candesartan provided more protection, in terms of no significant change in albuminuria (vs. 25-fold increase with hydralazine), regression of cardiac hypertrophy, frequency of vascular lesions and histological indices of renal injury maintained within control values. In conclusion, candesartan cilexetil prevented L-NAME-exacerbated hypertension and associated cardio-renal injury in young SHR, the beneficial effects exceeding those of hydralazine.

Candesartan cilexetil reduces graft arteriosclerosis in aortic transplantation model in rat

To date established treatment of transplant arteriosclerosis is basically missing and there is a need for new therapeutic approaches. Angiotensin II (Ang II) and Ang II receptor type 1 (AT 1) are present in the vascular wall. Blocking of the AT 1 receptor by pharmacological agents may inhibit damaging effects of Ang II on endothelial and smooth muscle cells. The purpose of the study was to evaluate the effect of the AT 1 receptor blocker Candesartan cilexetil on the development of graft arteriosclerosis in a rat aortic transplant model. Two strain combinations were used for aortic transplantation: DA to PVG; and PVG to PVG. The animals received Candesartan cilexetil treatment (9.5±1.4 mg/kg/day) for 8 weeks. Candesartan cilexetil treatment reduced neointimal formation both in allografts (Qint 30.2±8.8% vs. 22.1±8.7%, P<0.05) and in isografts (Qint 15.5±4.4% vs. 6.7±3.3%, P=0.0001). Blocking of the AT 1 receptor signalling by Candesartan cilexetil was also associated with a reduced expression of TGF-β1. Macrophage infiltration was not affected by the treatment. Candesartan cilexetil treatment leads to reduced neointimal formation in aortic transplant. The positive effect of the drug might be partly explained by a reduction of TGF-β1 expression in the grafts. Candesartan treatment may provide another possibility for prevention of transplant arteriosclerosis and chronic rejection.

Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure

OBJECTIVESTo evaluate the effects of an angiotensin (Ang II) type 1 receptor antagonist on immune markers in patients with congestive heart failure (CHF).BACKGROUNDAng II stimulates production of immune factors via the Ang II type 1 receptor in vitro, and the long-term effects of Ang II type 1 receptor antagonists on plasma markers of immune activation are unknown in patients with CHF.METHODSTwenty-three patients with mild to moderate CHF with left ventricular dysfunction were randomly divided into two groups: treatment with Ang II type 1 receptor (candesartan cilexetil) (n = 14) or placebo (n = 9). We measured plasma levels of immune factors such as tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). We also measured plasma levels of the neurohumoral factors such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP), a biological marker of ANP and BNP.RESULTSPlasma levels of TNFalpha, IL-6, sICAM-1 and sVCAM-1 were increased in the 23 CHF patients compared with normal subjects and significantly decreased after 14 weeks of candesartan cilexetil treatment, but did not change in the placebo group. Plasma levels of BNP, which is a marker of ventricular injury, significantly decreased, and the molar ratio of plasma cGMP to cardiac natriuretic peptides (ANP + BNP) was significantly increased after candesartan cilexetil treatment, but did not change in the placebo group.CONCLUSIONSThese findings suggest that 14 weeks of treatment with an Ang II type 1 receptor antagonist (candesartan cilexetil) decreased plasma levels of the immune markers such as TNFalpha, IL-6, sICAM-1 and sVCAM-1 and that it improved the biological compensatory action of endogenous cardiac natriuretic peptides in patients with mild to moderate CHF.

Efficacy and Tolerability of Candesartan Cilexetil Monotherapy or in Combination with Other Antihypertensive Drugs

Objective: To evaluate the efficacy and tolerability of different dosages of candesartan cilexetil administered as monotherapy or in combination with any pre-existing but insufficient antihypertensive treatment. The effects of candesartan cilexetil treatment on quality of life were also investigated.