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1.  Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report 
Background
Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.
Methods
We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.
Results
After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.
Conclusions
Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.
Trial registration
UMIN-CTR: UMIN000010142
doi:10.1186/1475-2840-12-71
PMCID: PMC3663745  PMID: 23635096
Candesartan; Angiotensin receptor blockers; Type 2 diabetes mellitus; Inflammatory parameters; Pulse pressure
2.  Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome 
Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.
PMCID: PMC2922318  PMID: 20730073
albuminuria; ambulatory blood pressure; calcium channel blockers; carotid intima-media thickness
3.  Peripherally administered Angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo 
Angiotensin II AT1 receptor blockers (ARBs) are commonly used in the clinical treatment of hypertension. Subcutaneous or oral administration of the ARB candesartan inhibits brain as well as peripheral AT1 receptors, indicating transport across the blood brain barrier. Pretreatment with candesartan profoundly modifies the response to stress. The ARB prevents the peripheral and central sympathetic activation characteristic of isolation stress and abolishes the activation of the hypothalamic-pituitary-adrenal axis during isolation. In addition, candesartan prevents the isolation-induced decrease in cortical corticotropin-releasing factor 1 and benzodiazepine receptors induced by isolation. When administered before cold-restraint stress, candesartan totally prevents the production of gastric ulcerations. This preventive effect of candesartan is the consequence of profound anti-inflammatory effects, reduction of sympathetic stimulation, and preservation of blood flow to the gastric mucosa. The ARB does not reduce the hypothalamic-pituitary-adrenal axis stimulation during cold-restraint. Preservation of the effects of endogenous glucocorticoids is essential for protection of the gastric mucosa during cold-restraint. Administration of the ARB to non-stressed rats decreases anxiety in the elevated plus-maze. Our results demonstrate that Angiotensin II, through AT1 receptor stimulation, is a major stress hormone, and that ARBs, in addition to their anti-hypertensive effects, may be considered for the treatment of stress-related disorders.
doi:10.1196/annals.1410.006
PMCID: PMC2659765  PMID: 19120129
Renin Angiotensin System; inflammation; brain; gastric ulcers; Corticotropin releasing hormone; GABAA; sympathetic system
4.  Comparative effect of olmesartan and candesartan on lipid metabolism and renal function in patients with hypertension: a retrospective observational study 
Background
Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g., cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal function.
Methods
We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively.
Results
After adjustment, there were no statistically significant differences in all covariates between olmesartan and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and candesartan users were women, respectively. There were no statistically significant differences in mean values for all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users. Other parameters of lipid profile and renal function showed no statistically significant difference in the change from baseline to during the exposure period between olmesartan and candesartan users.
Conclusions
In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG, with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant changes in the levels of all test parameters between baseline and during the exposure period with both drugs. These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal function is small, and that they can be safely used in patients with hypertension.
doi:10.1186/1475-2840-10-74
PMCID: PMC3163179  PMID: 21827713
angiotensin II receptor blocker (ARB); olmesartan; candesartan; lipid metabolism; renal function; retrospective observational study
5.  Differential clinical profile of candesartan compared to other angiotensin receptor blockers 
The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1]) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.
doi:10.2147/VHRM.S22591
PMCID: PMC3253768  PMID: 22241949
angiotensin receptor blockers; candesartan; candesartan cilexetil; clinical trials; efficacy studies; safety; blood pressure
6.  Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke 
Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs.
doi:10.3390/ijms140918899
PMCID: PMC3794813  PMID: 24065095
stroke; telmisartan; irbesartan; candesartan; high mobility group box 1; receptor for advanced glycation end-products
7.  Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice 
Neuropsychopharmacology  2012;37(13):2817-2829.
Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT1R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFβ1 while increasing expression of TGFβ3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT1R-blocking and PPARγ activation properties may have therapeutic value in treating TBI.
doi:10.1038/npp.2012.152
PMCID: PMC3499714  PMID: 22892395
traumatic brain injury; candesartan; TGFβ; inflammation; neuroprotection; PPARγ; molecular & cellular neurobiology; neuropharmacology; neurodegeneration/neuroprotection; learning & memory; traumatic brain injury; candesartan; TGF-beta; neuroprotection; inflammation; PPARgamma
8.  ANTI-INFLAMMATORY EFFECTS OF ANGIOTENSIN RECEPTOR BLOCKERS IN THE BRAIN AND THE PERIPHERY 
Cellular and molecular neurobiology  2009;29(6-7):781-792.
SUMMARY
In addition to regulating blood pressure, Angiotensin II exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT1 receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Angiotensin II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation.
We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case.
We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT1 receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain.
doi:10.1007/s10571-009-9368-4
PMCID: PMC2718067  PMID: 19259805
9.  Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress 
Behavioural Brain Research  2012;232(1):84-92.
Centrally acting Angiotensin II AT1 receptor blockers (ARBs) protect from stress-induced disorders and decrease anxiety in a model of inflammatory stress, the systemic injection of bacterial endotoxin lipopolysaccharide (LPS). In order to better understand the anxiolytic effect of ARBs, we treated rats with LPS (50 µg/kg) with or without three days of pretreatment with the ARB candesartan (1 mg/kg/day), and studied cortical benzodiazepine (BZ) and corticotrophin-releasing factor (CRF) receptors. We compared the cortical BZ and CRF receptors expression pattern induced by LPS with that produced in restraint stress. Inflammation stress produced a generalized increase in cortical BZ1 receptors and reduced mRNA expression of the GABAA receptor γ2 subunit in cingulate cortex; changes were prevented by candesartan pretreatment. Moreover, restraint stress produced similar increases in cortical BZ1 receptor binding, and candesartan prevented these changes. Treatment with candesartan alone increased cortical BZ1 binding, and decreased γ2 subunit mRNA expression in the cingulate cortex. Conversely, we did not find changes in CRF1 receptor expression in any of the cortical areas studied, either after inflammation or restraint stress. Cortical CRF2 receptor binding was undetectable, but CRF2 mRNA expression was decreased by inflammation stress, a change prevented by candesartan. We conclude that stress promotes rapid and widespread changes in cortical BZ1 receptor expression; and that the stress-induced BZ1 receptor expression is under the control of AT1 receptor activity. The results suggest that the anti-anxiety effect of ARBs may be associated with their capacity to regulate stress-induced alterations in cortical BZ1 receptors.
doi:10.1016/j.bbr.2012.03.041
PMCID: PMC3372928  PMID: 22503782
Angiotensin II AT1 receptor blockers; Cortical benzodiazepine receptors; GABAA receptor subunits; CRF receptors; Anxiety; Stress
10.  Effects of Angiotensin II Type 1 receptor blocker and adiponectin on adipocyte dysfunction in stroke-prone spontaneously hypertensive rats 
Background
Hypoadiponectinemia in lipoatrophy may be related to worsening of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). One of the beneficial effects of candesartan (Angiotensin II Type 1 receptor blocker) for preventing hypertension may be increasing of adiponectin due to improvement of adipocyte dysfunction. In this study, we determined the effects of candesartan or adiponectin on pathophysiologic features and adipocyte dysfunction in SHRSP.
Methods
Candesartan was administered to male SHRSP from 16 to 20 weeks of age (2 mg/kg/day). Adiponectin was cloned and intravenously administered to male SHRSP from 16 to 20 weeks of age. We examined biological parameters, as well as the expression and release of adipokines.
Results
The SHRSP exhibited severe atrophy of visceral fat and progression of severe hypertension. The expression and release of leptin and adiponectin were impaired at 6 and 20 weeks of age. Candesartan suppressed the development of lipoatrophy and reduced the incidence of stroke at 20 weeks of age. Candesartan also enhanced the expression of adiponectin and leptin by inducing the overexpression of peroxisome proliferator activated receptor γ. Circulating level of leptin was significantly higher in candesartan group than in the control group, whereas adiponectin was similar in both groups. Intravenous administration of adiponectin resulted in enhancement of adiponectin expression in adipose tissue, but no remarkable effects were found in pathophysiology in SHRSP.
Conclusions
Our results indicate that candesartan protects against hypertension and adipocyte dysfunction in SHRSP. The induction of leptin expression appeared to be important factor in the inhibition of stroke lesions, whereas adiponectin was not a major regulator of blood pressure in SHRSP with genetic hypertension. Further studies are needed to elucidate the role of the renin–angiotensin system in adipose tissue dysfunction in relation to hypertensive end-organ damage.
doi:10.1186/1476-511X-12-108
PMCID: PMC3750705  PMID: 23876211
Stroke-prone spontaneously hypertensive rats; Adipose tissue; Renin–angiotensin system; Angiotensin II type I receptor blocker; Lipoatrophy; Adipokines
11.  Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan 
The angiotensin II type 1 (AT1) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT1 receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT1 receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT1 receptor (Tyr113, Lys199 and Gln257), the hydrogen bonding between the oxadiazole of azilsartan-Gln257 is stronger than that between the tetrazole of candesartan-Gln257, according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan–Gln257 interaction and that azilsartan had a stronger interaction with Gln257 than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT1 receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP-lowering efficacy compared with candesartan and other ARBs.
doi:10.1038/hr.2012.147
PMCID: PMC3951115  PMID: 23034464
azilsartan; candesartan; inverse agonist; oxadiazole
12.  Difference in the effects of switching from Candesartan to Olmesartan or Telmisartan to Olmesartan in hypertensive patients with type 2 diabetes: the COTO study 
Purpose
This open-label controlled study compared the therapeutic efficacy of three representative angiotensin II receptor blockers (ARBs) in hypertensive patients with type 2 diabetes attending a hospital outpatient clinic. The primary measure in this study was morning home blood pressure (BP).
Patients and methods
Two studies were done concurrently to investigate the effects of switching from two different ARBs to olmesartan. Patients prescribed candesartan (8 mg once daily in the morning) or telmisartan (40 mg once daily in the morning) for 16 weeks were switched to olmesartan (20 mg once daily in the morning) for 16 weeks. Then, they were switched back to candesartan (CO group) or telmisartan (TO group) for another 16 weeks.
Results
Data from all patients in the CO group (n=165) and the TO group (n=152) were analyzed. Clinic and morning home BP and urinary albumin levels showed a significant decrease from baseline at 16 weeks after switching to olmesartan in both the CO and the TO group (clinic BP, morning home diastolic BP, and urinary albumin, P<0.05; morning home systolic BP, P<0.01). In contrast, clinic BP, morning home BP, and urinary albumin were significantly increased again 16 weeks after switching back to candesartan or telmisartan (clinic BP, morning home diastolic BP, and urinary albumin, P<0.05; morning home systolic BP, P<0.01). No subjects experienced an adverse reaction that required withdrawal from the study. No adverse reactions attributable to the study drugs were observed.
Conclusion
Olmesartan is a promising ARB for BP control in hypertensive type 2 diabetics.
doi:10.2147/DDDT.S53253
PMCID: PMC3933665  PMID: 24600204
type 2 diabetes; morning home blood pressure; albuminuria; olmesartan
13.  Olmesartan is More Effective Than Other Angiotensin Receptor Antagonists in Reducing Proteinuria in Patients With Chronic Kidney Disease Other Than Diabetic Nephropathy☆ 
Background
Angiotensin II receptor antagonists (ARBs) have a protective effect in patients with chronic kidney disease (CKD) by suppressing progression, possibly by controlling hypertension. One marker of progression in such patients is the degree of proteinuria.
Objective
We aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy.
Methods
Data were retrieved from medical records of patients with a diagnosis of CKD (serum creatinine [Cre] <3.0 mg/dL [265.2 μmol/L] and urinary protein of 0.3–3.5 g/g Cre) who were treated with ARBs and those with diabetic nephropathy were excluded. Blood pressure, serum Cre, urinary protein, urinary Cre, and estimated glomerular filtration rate were measured before the research began and at 1, 3, 6, 12, and 24 months after the ARB treatment was started.
Results
Forty-four patients completed the research protocol. Of these, 10 took olmesartan, 13 took losartan, 9 took candesartan, 9 took valsartan, and 3 took telmisartan. Systolic blood pressure was decreased in all cases. The extent of this decrease 1 month after starting ARB treatment was greater for olmesartan than for candesartan (P < 0.05), and after 2 years, it was greater than for losartan (P < 0.05). Diastolic blood pressure decreased in all patients; this decrease was significantly greater with olmesartan 1 month after treatment started than with candesartan (P < 0.05). Olmesartan significantly decreased daily urinary protein compared with that with the other ARBs during follow-up. This decrease 1 month after starting ARB treatment was greater for olmesartan than losartan, valsartan, and candesartan (P < 0.01, P < 0.01, and P < 0.05, respectively), and after 2 years, this effect was still significant (P < 0.05, P < 0.01, and P < 0.01, respectively).
Conclusions
Olmesartan is more effective in reducing urinary protein than other ARBs, suggesting that the renal protective effects of olmesartan may be better than those of other ARBs.
doi:10.1016/j.curtheres.2013.02.002
PMCID: PMC3862195  PMID: 24384547
angiotensin II receptor antagonist; nondiabetic chronic kidney disease; olmesartan; proteinuria
14.  Improved Early-Phase Insulin Response after Candesartan Treatment in Hypertensive Patients with Impaired Glucose Tolerance 
As the effect of renin-angiotensin system (RAS) blockade on β-cells in clinical situations remains unclear, new evidence has been presented that angiotensin-converting enzyme (ACE) inhibitors and angiotensin ‖ receptor blockers (ARBs) may delay or prevent the development of insulin resistance and diabetes through novel mechanisms. This study aimed to determine the effects of ARBs on insulin excretion by β-cells. Hypertensive patients with impaired glucose tolerance were randomly divided into two groups: group A (n = 6), which received 8 mg/day of oral candesartan for three months, and controls (n = 6). Before and after administration, a 75 g oral glucose tolerance test was conducted to compare various parameters. No significant differences in age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, or fasting immunoreactive insulin (IRI) were identified between the groups before administration. After three months, there were no significant changes in BMI, SBP, and DBP for the controls and in BMI and DBP for group A. However, SBP was significantly decreased from 144 ± 2.6 mmHg to 125 ± 4.6 mmHg in group A. Insulinogenic index tended to be slightly decreased for controls, but was significantly increased from 0.32 ± 0.0 to 0.47 ± 0.1 for group A. No significant changes in HOMA-R were identified in either group. To the best of our knowledge, no previous studies have documented a RAS inhibitor improving early-phase insulin response; thus, the present study may be the first of its kind.
doi:10.1080/10641960802269927
PMCID: PMC2495588  PMID: 18633754
candesartan; IGT; insulinogenic index; insulin secretion
15.  Comparative Effects of Angiotensin Receptor BlockadeandACE Inhibition on the Fibrinolytic and Inflammatory Responses to Cardiopulmonary Bypass 
Clinical pharmacology and therapeutics  2012;91(6):10.1038/clpt.2011.356.
The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation following cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to greater extent than ARB in patients undergoing CPB.One week to five days prior to surgery, patients were randomized to ramipril 5mg/day,candesartan 16mg/day or placebo.ACE inhibition increased intraoperative bradykinin and tissue-type plasminogen activator (t-PA) concentrations compared to ARB. Both ACE inhibition and ARB decreased plasma transfusion compared to placebo, but only ACE inhibition decreased length of stay. Neither ACE inhibition nor ARB significantly affectedplasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-6, IL-8, or IL-10 concentrations. ACE inhibition enhanced intraoperative fibrinolysis without increasing red cell transfusion risk. In contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARB may be safely continued until the day of surgery.
doi:10.1038/clpt.2011.356
PMCID: PMC3822756  PMID: 22549281
Angiotensin-converting enzyme inhibition; angiotensin receptor blocker; renin-angiotensin system; cardiac surgery; cardiopulmonary bypass; plasminogen activator; interleukin; bradykinin
16.  Angiotensin II receptor blockers decreased blood glucose levels: a longitudinal survey using data from electronic medical records 
Background
A beneficial effect on glucose metabolism is reported with angiotensin receptor blocker (ARB) treatment of hypertension. The effect on blood glucose level during the course of treatment with ARBs in clinical cases is uncertain. Our objectives were to survey the changes in glucose and HbA1c levels in patients with hypertension over a one-year period, and to study the correlations between these values and the time after the start of ARB therapy.
Methods
We conducted a retrospective longitudinal survey of blood glucose and HbA1c measurements in Japanese patients aged ≥20 years with newly diagnosed hypertension but without diabetes, who had received ARB monotherapy with candesartan cilexetil, losartan potassium, olmesartan medoxomil, telmisartan, or valsartan during the period from December 2004 to November 2005. Data including 2465 measurements of non-fasting blood glucose in 485 patients and 457 measurements of HbA1c in 155 patients were obtained from electronic medical records of Nihon University School of Medicine. Linear mixed effects models were used to analyze the relationship between these longitudinal data of blood examinations and covariates of patient age, sex, medication, and duration of ARB therapy.
Results
Casual blood glucose level was associated with the duration of treatment (P < 0.0001), but not with age, sex, or medication. Blood glucose level was significantly decreased during the periods of 0~3 months (P < 0.0001) and 3~6 months (P = 0.0081) compared with baseline, but was not significantly different between 6~12 months and baseline. There was no association between HbA1c level and covariates of sex, age, medication and duration of treatment.
Conclusion
Our findings provide new clinical evidence that the effects of ARBs on glucose metabolism may change during the course of treatment, suggesting a blood glucose-lowering effect in the short-term after the start of treatment.
doi:10.1186/1475-2840-6-26
PMCID: PMC2098751  PMID: 17903269
17.  Drug Repurposing for Vascular Protection After Acute Ischemic Stroke 
The attempts to develop new treatments for acute ischemic stroke have been fraught with costly and spectacularly disappointing failures. Repurposing of safe, older drugs provides a lower risk alternative. Vascular protection is a novel strategy for improving stroke outcome. Promising targets for vascular protection after stroke have been identified, and several of these targets can be approached with “repurposed” old drugs, including statins, angiotensin receptor blockers (ARBs), and minocycline.
We tested the vascular protection (ability to reduce hemorrhagic transformation) of three marketed drugs (candesartan, minocycline, and atorvastatin) in the experimental stroke model using three different rat strains [Wistar, spontaneously hypertensive rats (SHR) and type 2 diabetic Goto-Kakizaki (GK) rats]. All agents decreased the infarct size, improved the neurological outcome and decreased bleeding. Mechanisms identified include inhibition of MMP-9, activation of Akt, and increased expression of proangiogenic growth factors. Premorbid vascular damage (presence of either diabetes or hypertension) increased the likelihood of vascular injury after ischemia and reperfusion and improved the response to vascular protection.
doi:10.1007/978-3-7091-0693-8_49
PMCID: PMC3166853  PMID: 21725771
Stroke; Drug repurposing; Hemorrhagic transformation
18.  Effect of candesartan monotherapy on lipid metabolism in patients with hypertension: a retrospective longitudinal survey using data from electronic medical records 
Background
Studies focusing on the add-on effects of angiotensin II type 1 receptor blockers (ARBs) other than their antihypertensive effect are receiving attention. However, the effects of prolonged administration of ARBs on lipid metabolism in clinical cases are unclear. Our aims were to survey the changes in plasma lipid profile in patients with hypertension over a one-year period, and to examine the correlations between these values and the time after the start of ARB monotherapy with candesartan.
Methods
We carried out candesartan monotherapy in patients with mild to moderate hypertension and examined the longitudinal changes in plasma lipid profile. Data from 405 patients for triglyceride (TG), 440 for total cholesterol (TC), 313 for high density lipoprotein cholesterol (HDL-C) and 304 for low density lipoprotein cholesterol (LDL-C) were obtained from the electronic medical records (EMRs) in the Clinical Data Warehouse (CDW) of Nihon University School of Medicine (NUSM). The inverse probability of treatment weighting (IPTW) method (calculated from the inverse of the propensity score) was used to balance the covariates and reduce bias in each treatment duration. Linear mixed effects models were used to analyse the relationship between these longitudinal data of blood examinations and covariates of patient sex, age, diagnosis of diabetes mellitus (DM) and duration of candesartan monotherapy.
Results
Plasma HDL-C level was associated with sex, duration of treatment, and interaction of sex and treatment duration, but not with age or diagnosis of DM. HDL-C level was significantly decreased during the 6~9 months period (p = 0.0218) compared with baseline. TG and TC levels were associated with sex, but not with age, diagnosis of DM or treatment duration. LDL-C level was not associated with any covariate. Analysis of the subjects divided by sex revealed a decrease in HDL-C in female subjects (during the 6~9 months period: p = 0.0054), but not in male subjects.
Conclusions
Our study revealed that administration of candesartan slightly decreased HDL-C in female subjects. However, TG, TC and LDL-C levels were not influenced by candesartan monotherapy. Candesartan may be safely used for patients with hypertension with respect to lipid metabolism, because the effect of candesartan on lipids may be small.
doi:10.1186/1475-2840-9-38
PMCID: PMC2933671  PMID: 20712859
19.  Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo 
Atherosclerosis  2008;202(1):76-83.
Introduction
Toll-like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis, atherosclerosis, and arthritis. TLR2 and TLR4 expression is upregulated in the inflammatory diseases. Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT1R. Angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to also have anti-inflammatory effects. Thus, we investigated whether an ARB exerts anti-inflammatory effects via inhibiting TLR2 and TLR4 expression.
Methods and results
Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan. Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced TLR2 and TLR4 expression of both mRNA and protein levels (P < 0.05 vs. control) along with decrease in the activity of NF-κB and the expression of IL-1β, IL-6, TNF-α, and MCP-1. Furthermore, candesartan treated mice show decreased TLR2 and TLR4 expression compared to vehicle control mice.
Conclusion
Pam3CSK4 and LPS induced TLR2 and TLR4 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo. Thus, we define a novel pathway by which candesartan could induce anti-inflammatory effects.
doi:10.1016/j.atherosclerosis.2008.04.010
PMCID: PMC2676176  PMID: 18495130
Toll-like receptors; LPS; Angiotensin receptor blocker; Monocytes; Nuclear factor-kappa B; Inflammation
20.  Systemic candesartan reduces brain angiotensin II via downregulation of brain renin–angiotensin system 
The renin–angiotensin system has an important function in the regulation of blood pressure as well as in pathophysiological processes in the central nervous system. We examined the effects of the angiotensin receptor blocker candesartan (10 mg kg−1 per day, p.o.) on brain angiotensin II levels in angiotensin II-infused hypertensive rats. Angiotensin II or vehicle was infused subcutaneously for 14 days in Sprague–Dawley rats. Angiotensin II infusion resulted in increased blood pressure, an effect that was blocked by candesartan treatment. There was no effect of the angiotensin II infusion on Angiotensin II levels in the brain or on blood–brain barrier permeability. Brain tissue angiotensinogen and angiotensin converting enzyme mRNA levels were not changed by angiotensin II infusion but were decreased by candesartan treatment. At 2 weeks of treatment, CV11974, an active form of candesartan, was detectable in the plasma but was not detectable in brain tissue. These data suggest that treatment with candesartan decreases brain angiotensin II by decreasing brain angiotensinogen and angiotensin converting enzyme gene expression.
doi:10.1038/hr.2009.200
PMCID: PMC2818705  PMID: 19942928
angiotensin II; AT1 type 1 receptor; brain; candesartan
21.  Angiotensin II AT1 Receptor Blockade Ameliorates Brain Inflammation 
Neuropsychopharmacology  2010;36(4):857-870.
Brain inflammation has a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post-traumatic stress disorder, Parkinson's and Alzheimer's disease, and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting angiotensin II AT1 receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus, and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells, and cerebral microvascular endothelial cells. ARBs are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.
doi:10.1038/npp.2010.225
PMCID: PMC3055735  PMID: 21150913
innate immune response; lipopolysaccharide; proinflammatory cytokines; microglia activation; sickness behavior; molecular & cellular neurobiology; mood/anxiety/stress disorders; neuropharmacology; neurodegeneration/neuroprotection; innate immune response; microglia activation; lipopolysaccharide; sickness behavior; pro-inflammatory cytokines
22.  Candesartan cilexetil in the treatment of chronic heart failure 
The prevalence of heart failure is ever increasing around the world, particularly due to aging populations. Despite improvements in treatment over the last 20 years, the prognosis for heart failure remains poor. Among the treatments recommended for chronic heart failure, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are crucial, provided of course that they are not contraindicated. However, angiotensin II receptor blockers (ARBs) can also be a beneficial treatment option. Candesartan is a particular ARB, characterized by a strong binding affinity to the angiotensin II type 1 receptor and slow dissociation. The benefits of candesartan have been demonstrated by the CHARM programme, which showed that candesartan significantly reduces the incidence of cardiovascular death, hospital admissions for decompensated heart failure, and all-cause mortality in chronic heart failure patients with altered left ventricular systolic function, when added to standard therapies or as an alternative to ACE inhibitors when these are poorly tolerated. Furthermore, candesartan can protect against myocardial infarction, atrial fibrillation and diabetes. Tolerance to candesartan is good, but blood pressure and serum potassium and creatinine levels must be monitored.
PMCID: PMC2672439  PMID: 19436650
chronic heart failure; angiotensin II receptor blockers; candesartan; left ventricular systolic function
23.  Differential pharmacology and benefit/risk of azilsartan compared to other sartans 
Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), was recently approved by regulatory authorities for treatment of hypertension and is the 8th ARB to join the clinical market. This article discusses the medical reasons for introducing a new AT1 receptor blocker and reviews the experimental and clinical studies that have compared the functional properties of azilsartan to those of other ARBs. The main question addressed is: Does azilsartan have distinguishing features that should motivate choosing it over any of the other sartans for use in clinical practice? Based on studies conducted to date in hypertensive patients without serious comorbidities, azilsartan appears to be characterized by a superior ability to control 24-hour systolic blood pressure (BP) relative to other widely used ARBs including valsartan, olmesartan, and candesartan, and presumably others as well (eg, losartan). Compared to these other ARBs, azilsartan may increase the BP target control and response rate by an absolute value of 8%–10%. Greater antihypertensive effects of azilsartan might be due in part to its unusually potent and persistent ability to inhibit binding of angiotensin II to AT1 receptors. Preclinical studies have indicated that azilsartan may also have potentially beneficial effects on cellular mechanisms of cardiometabolic disease and insulin sensitizing activity that could involve more than just blockade of AT1 receptors and/or reduction in BP. However, the clinical relevance of these additional actions is unknown. Given that the general ability of antihypertensive drugs to protect against target organ damage is largely mediated by their ability to decrease BP, the enhanced antihypertensive effects of azilsartan should serve to justify clinical interest in this ARB relative to other molecules in the class that have a lower capacity to reduce BP.
doi:10.2147/VHRM.S22595
PMCID: PMC3295635  PMID: 22399858
azilsartan; azilsartan medoxomil; angiotensin II type 1 receptor blockers; angiotensins; hypertension; TAK-491; TAK-536; candesartan; olmesartan; valsartan; losartan; telmisartan; irbesartan; eprosartan
24.  Effects of losartan vs candesartan in reducing cardiovascular events in the primary treatment of hypertension 
Journal of Human Hypertension  2009;24(4):263-273.
Although angiotensin receptor blockers have different receptor binding properties no comparative studies with cardiovascular disease (CVD) end points have been performed within this class of drugs. The aim of this study was to test the hypothesis that there are blood pressure independent CVD-risk differences between losartan and candesartan treatment in patients with hypertension without known CVD. Seventy-two primary care centres in Sweden were screened for patients who had been prescribed losartan or candesartan between the years 1999 and 2007. Among the 24 943 eligible patients, 14 100 patients were diagnosed with hypertension and prescribed losartan (n=6771) or candesartan (n=7329). Patients were linked to Swedish national hospitalizations and death cause register. There was no difference in blood pressure reduction when comparing the losartan and candesartan groups during follow-up. Compared with the losartan group, the candesartan group had a lower adjusted hazard ratio for total CVD (0.86, 95% confidence interval (CI) 0.77–0.96, P=0.0062), heart failure (0.64, 95% CI 0.50–0.82, P=0.0004), cardiac arrhythmias (0.80, 95% CI 0.65–0.92, P=0.0330), and peripheral artery disease (0.61, 95% CI 0.41–0.91, P=0.0140). No difference in blood pressure reduction was observed suggesting that other mechanisms related to different pharmacological properties of the drugs may explain the divergent clinical outcomes.
doi:10.1038/jhh.2009.77
PMCID: PMC2834374  PMID: 19890371
epidemiology; heart failure; cardiovascular diseases; blood pressure
25.  Carbonyl stress induces hypertension and cardio–renal vascular injury in Dahl salt-sensitive rats 
Hypertension Research  2013;36(4):361-367.
One major precursor of carbonyl stress, methylglyoxal (MG), is elevated in the plasma of chronic kidney disease (CKD) patients, and this precursor contributes to the progression of vascular injury, hypertension and renal injury in diabetic nephropathy patients. This molecule induces salt-sensitive hypertension via a reactive oxygen species-mediated pathway. We examined the role of MG in the pathogenesis of hypertension and cardio–renal injury in Dahl salt-sensitive (Dahl S) rats, which is a rat model of CKD. Nine-week-old Dahl S rats were fed a 1% NaCl diet, and 1% MG was added to their drinking water for up to 12 weeks. Blood pressure and cardio–renal injuries were compared with rats treated with tap water alone. The angiotensin II receptor blocker (ARB), candesartan (10 mg kg−1 day−1), was administered to MG Dahl S rats to determine the impact of this drug on the pathogenesis of MG-induced CKD. A progressive increase in systolic blood pressure was observed (123±1–148±5 mm Hg) after 12 weeks of MG administration. MG administration significantly increased urinary albumin excretion, glomerular sclerosis, tubular injury, myocardial collagen content and cardiac perivascular fibrosis. MG also enhanced the renal expression of Nɛ-carboxyethyl-lysine (an advanced glycation end product), 8-hydroxydeoxyguanosine (a marker of oxidative stress), macrophage (ED-1) positive cells (a marker of inflammation) and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity. Candesartan treatment for 4 weeks significantly reduced these parameters. These results suggest that MG-induced hypertension and cardio–renal injury and increased inflammation and carbonyl and oxidative stress, which were partially preventable by an ARB.
doi:10.1038/hr.2012.204
PMCID: PMC3619051  PMID: 23364337
carbonyl stress; chronic kidney disease; methylglyoxal; salt sensitivity

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