Azelnidipine Treatment Research Articles

Azelnidipine protects HL-1 cardiomyocytes from hypoxia/reoxygenation injury by enhancement of NO production independently of effects on gene expression.

It remains to be elucidated whether Ca2+ antagonists induce pharmacological preconditioning to protect the heart against ischemia/reperfusion injury. The aim of this study was to determine whether and how pretreatment with a Ca2+ antagonist, azelnidipine, could protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury in vitro. Using HL-1 cardiomyocytes, we studied effects of azelnidipine on NO synthase (NOS) expression, NO production, cell death and apoptosis during H/R. Action potential durations (APDs) were determined by the whole-cell patch-clamp technique. Azelnidipine enhanced endothelial NOS phosphorylation and NO production in HL-1 cells under normoxia, which was abolished by a heat shock protein 90 inhibitor, geldanamycin, and an antioxidant, N-acetylcysteine. Pretreatment with azelnidipine reduced cell death and shortened APDs during H/R. These effects of azelnidipine were diminished by a NOS inhibitor, L-NAME, but were influenced by neither a T-type Ca2+ channel inhibitor, NiCl2, nor a N-type Ca2+ channel inhibitor, ω-conotoxin. The azelnidipine-induced reduction in cell death was not significantly enhanced by either additional azelnidipine treatment during H/R or increasing extracellular Ca2+ concentrations. RNA sequence (RNA-seq) data indicated that azelnidipine-induced attenuation of cell death, which depended on enhanced NO production, did not involve any significant modifications of gene expression responsible for the NO/cGMP/PKG pathway. We conclude that pretreatment with azelnidipine protects HL-1 cardiomyocytes against H/R injury via NO-dependent APD shortening and L-type Ca2+ channel blockade independently of effects on gene expression.

A Retrospective Study to Evaluate Real-world Evidence of Azelnidipine in Indian Patients (REDEFINE Study).

Azelnidipine, a selective calcium channel blocker, effectively lowers blood pressure (BP) and heart rate (HR) in hypertensive patients, as demonstrated in a retrospective real-world evidence (RWE) study in Indian patients. This was a retrospective cohort study that included 882 patients aged 18 years or older who had been on azelnidipine treatment for the last 3 months for mild to moderate hypertension (HTN). A structured proforma was utilized to gather data from prescribing physicians to assess the efficacy of azelnidipine (8 and 16 mg) as monotherapy or in combination with other antihypertensive drugs. The primary endpoints of the study were to capture changes in systolic blood pressure (SBP) and diastolic BP (DBP) from baseline to the subsequent visits (4 and 12 weeks), while the secondary endpoints were to measure similar changes in the diabetic group and to estimate the proportion of patients achieving target BP of <130/80 mm Hg and <140/90 mm Hg, respectively. The overall mean reduction of systolic/diastolic BP from baseline to 12 weeks was 13.92/7.91 mm Hg (p-value < 0.0001). The mean reduction of systolic/diastolic BP from baseline to 12 weeks was 11.77/7.43 mm Hg (p-value < 0.0001) in newly diagnosed HTN patients, while in known cases of HTN, it was 16.50/8.48 mm Hg (p-value < 0.0001). In the diabetic group, the mean reduction was 15.35/8.69 mm Hg (p-value < 0.0001). Overall the study showed that in 44 (4.99%) and 408 (46.26%) patients, target BP of <130/80 mm Hg and <140/90 mm Hg, respectively was achieved. The mean change in HR from baseline was a reduction of 5.22 beats/minute. Azelnidipine can be an effective antihypertensive drug to treat mild to moderate HTN in Indian patients.

Potential protective effects of Azelnidipine against cerebral ischemia-reperfusion injury in male rats.

This study was performed to evaluate the neuroprotective effect of Azelnidipine in cerebral ischemia/reperfusion and to envisage its mechanisms. Twenty-eight adult male Sprague-Dawley rats weighing 200-300 g were randomized into 4 groups (7 rats in each group). Sham (neck dissection without bilateral common carotid artery occlusion), control (30 minutes of bilateral common carotid artery occlusion and reperfusion for 1 hour), vehicle (identical volume of 0.3% carboxymethylcellulose (CMC) orally every day then bilateral common artery occlusion and reperfusion), and Azelnipine-treated rats (7 days of Azelnidipine pretreatment 3 mg/kg/day followed by bilateral common carotid artery occlusion and reperfusion). In addition to brain infarct volume and histopathological assessment, the brain tissues were harvested to evaluate cerebral IL-6, IL-10, TNF-α, ICAM-1, NF-κB p65, and total antioxidant capacity levels. Cerebral levels of IL-6, IL-10, TNF-α, NF-κB p65, and ICAM-1, besides cerebral infarct volume, were significantly elevated in control and vehicle related to sham groups, while total antioxidant capacity was markedly reduced. Azelnidipine treatment resulted in remarkable upregulation of total antioxidant capacity; meanwhile, IL-6, TNF-α, NF-κB p65, and ICAM-1 showed a considerable reduction. Cerebral IL-10 levels were not affected by Azelnidipine pretreatment. Histologically, control and vehicle rats showed severe ischemic injury, which was greatly reversed by Azelnidipine treatment. The current study disclosed that Azelnidipine could markedly reduce cerebral infarct volume and ameliorate histopathological damage in male rats exposed to cerebral ischemia/reperfusion. The neuroprotective effects of Azelnidipine probably stemmed from its anti-inflammatory and antioxidative properties. Azelnidipine had no effect on cerebral IL-10 levels.

Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2

Epidemiological and mechanistic studies suggest that some US Food and Drug Administration (FDA)-approved drugs can reduce the incidence of cancer and inhibit tumor growth. Therefore, investigating FDA-approved drugs for cancer chemoprevention is a promising strategy. In this study, we screened FDA-approved drugs and found that azelnidipine, a Ca channel blocker widely used in the treatment of hypertension, inhibits the growth of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. We identified that MEK1/2 were direct targets of azelnidipine through pull-down assay and cellular thermal shift assay. Azelnidipine could suppress kinase activity of MEK1/2 through in vitro kinase assay. Hypophosphorylation of ERK1/2 decreased the levels of Cyclin D1/CDK6 in ESCC cells after azelnidipine treatment. More importantly, azelnidipine, like trametinib, inhibited the growth of ESCC in vivo. In conclusion, azelnidipine, a novel dual MEK1/2 inhibitor, exerted antitumor effects against ESCC cell lines and patient-derived xenograft in ESCC.

TDO2 modulates liver cancer cell migration and invasion via the Wnt5a pathway.

Liver cancer is a malignant cancer phenotype for which there currently remains a lack of reliable biomarkers and therapeutic targets for disease management. Tryptophan 2,3‑dioxygenase(TDO2), a heme‑containing polyoxygenase enzyme, is primarily expressed in cells of the liver and nervous systems. In the present study, through the combination of cancer bioinformatics and analysis of clinical patient samples, it was shown that TDO2 expression in liver cancer tissue samples was significantly higher than that in normal tissues, and liver cancer patients with high TDO2 expression had a poor prognosis. Mechanistic studies on liver cancer cells showed that TDO2 promoted cancer cell migration and invasion via signal transduction through the Wnt5a pathway. Such regulation impacted the expression of cancer‑associated biomarkers, such as matrix metalloprotease 7 (MMP7) and the cell adhesion receptor CD44. Treatment with a calcium channel blocker (azelnidipine) reduced TDO2 levels and inhibited liver cancer cell migration and invasion. A mouse xenograft cancer model showed that TDO2 promoted tumorigenesis. Furthermore, azelnidipine treatment to downregulate TDO2 also decreased liver cancer development in this mouse cancer model. TDO2 is thus not only a useful liver cancer biomarker but a potential drug target for management of liver cancer.

A case of complete atrioventricular block with extremely high blood concentration of azelnidipine

BackgroundAzelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.Case presentationIn the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.ConclusionsAzelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Azelnidipine treatment reduces the expression of Cav1.2 protein

AimsAzelnidipine, a third-generation dihydropyridine calcium channel blocker (DHP CCB), has a characteristic hypotensive effect that persists even after it has disappeared from the plasma, which is thought to be due to its high hydrophobicity. However, because azelnidipine is unique, it might have other unknown effects on L-type Cav1.2 channels that result in the long-lasting decrease of blood pressure. The aim of this study was to investigate the potential quantitative modification of Cav1.2 by azelnidipine. Main methodsHEK293 cells were used to express Cav1.2 channels. Immunocytochemical analysis was performed to detect changes in the surface expression of the pore-forming subunit of the Cav1.2 channel, Cav1.2α1c. Western blotting analysis was performed to evaluate changes in expression levels of total Cav1.2α1c and Cavβ2c. Key findingsThe surface expression of Cav1.2α1c was markedly reduced by treatment with azelnidipine, but not with other DHP CCBs (amlodipine and nicardipine). Results obtained with a dynamin inhibitor and an early endosome marker suggested that the reduction of surface Cav1.2α1c was not likely caused by internalization. Azelnidipine reduced the total amount of Cav1.2α1c protein in HEK293 cells and rat pulmonary artery smooth muscle cells. The reduction of Cav1.2α1c was rescued by inhibiting proteasome activity. In contrast, azelnidipine did not affect the amount of auxiliary Cavβ2c subunits that function as a chaperone of Cav1.2. SignificanceThis study is the first to demonstrate that azelnidipine reduces the expression of Cav1.2α1c, which might partly explain its long-lasting hypotensive effect.

Anti-hypertensive azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes

It is known that reactive oxygen species (ROS) are involved in the development of insulin resistance as well as pancreatic β-cell dysfunction both of which are often observed in type 2 diabetes. In this study, we evaluated the effects of azelnidipine, a calcium channel blocker, on ROS-mediated insulin resistance in adipocytes. When 3T3-L1 adipocytes were exposed to ROS, insulin-mediated glucose uptake was suppressed, but such phenomena were not observed in the presence of azelnidipine. Phosphorylation of insulin receptor and phosphorylation of Akt were suppressed by ROS, which was mitigated by azelnidipine treatment. Activation of the JNK pathway induced by ROS was also reduced by azelnidipine. Various inflammatory cytokine levels were increased by ROS, which was also suppressed by azelnidipine treatment. In contrast, adiponectin mRNA and secreted adiponectin levels were reduced by ROS, which was refilled by azelnidipine treatment. In conclusion, azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes.

Changes in left ventricular relaxation after azelnidipine treatment in hypertensive patients with diabetes: subanalysis of a prospective single-arm multicentre study

ObjectivesWe previously demonstrated that a calcium channel blocker, azelnidipine, improves left ventricular relaxation in patients with hypertension and diastolic dysfunction in a multicentre, Clinical impact of Azelnidipine on Left VentricuLar diastolic function and OutComes in patients with hypertension (CALVLOC) trial. The objectives of the present subanalysis were to investigate the differences in diastolic function in hypertensive patients with and without diabetes, and the efficacy of azelnidipine on diastolic function among them.DesignSubanalysis of a prospective single-arm multicentre study.Participants228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e′ velocity <8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes.InterventionsAdministration of 16 mg of azelnidipine for 8 months (range 6–10 months).Main outcome measuresSeptal e′ velocity before and at the end of the study.ResultsWhereas patients with diabetes (n=53, 23.2%) had lower systolic blood pressure (BP) than patients without diabetes (155±17 vs 161±16 mm Hg, p=0.03), they had lower e′ velocity (5.7±1.5 vs 6.1±1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e′ velocity similarly in patients with diabetes (5.7±1.5 to 6.3±1.5 cm/s, p=0.0003) and without diabetes (6.1±1.4 to 6.9±1.4 cm/s, p<0.0001). Increase in e′ velocity was not influenced by presence of diabetes, and patients with diabetes still had lower e′ velocity after treatment (p=0.006). There was a significant correlation between increase in e′ velocity and decrease in systolic BP (R=0.25, p=0.0001), which was not influenced by diabetes.ConclusionsComorbid diabetes could impair left ventricular relaxation independently in patients with hypertension, which might not be improved solely by BP lowering.

Azelnidipine suppresses the progression of aortic aneurysm in wild mice model through anti-inflammatory effects

Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an inflammation-mediated progression of aneurysmal disease is likely responsible for AA growth and eventual rupture. Unfortunately, there remains no reproducible and durable small animal model of aortic aneurysmal disease, the development of which would enable the investigation of the pathophysiology of this vexing condition. The first aim was to establish a useful wild-type mouse model of AA with low mortality. The second aim was to use this model to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect. Angiotensin II and β-aminopropionitrile (a lysyl oxidase inhibitor) were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic minipump for 4 weeks to generate a wild-type mouse model of AA. Concurrently, azelnidipine (a calcium channel blocker) or a placebo was administrated orally for 4 weeks. Mice were humanely killed and assessed at the end of the 4 weeks of pharmacologic manipulation. The combined infusion of angiotensin II and β-aminopropionitrile induced degenerative aneurysm of the thoracic and/or abdominal aorta (11/12; 92%). The majority of aneurysms were located in the distal aortic arch and suprarenal abdominal aorta. Although there was no difference in systolic blood pressure between the control and azelnidipine-treated groups, azelnidipine significantly reduced the incidence of AA (2/11; 18%). Azelnidipine treatment reduced the pathologic findings normally associated with aneurysm formation within the aortic wall. Azelnidipine also reduced the number of macrophage antigen-3 (MAC-3)-positive cells in the periaortic adipose tissue and reduced the gene expression levels of tumor necrosis factor-alpha and matrix metalloproteinase-2 and -9 within the aortic wall. This study demonstrates that combined treatment with angiotensin II and β-aminopropionitrile induces degenerative AAs in wild-type mice, and azelnidipine prevents aneurysm progression via its anti-inflammatory effect.

Inhibitory effects of azelnidipine tablets on morning hypertension.

BackgroundMorning hypertension is a risk factor for cardiovascular and cerebrovascular events. Furthermore, it is a useful measure for definitive diagnosis of hypertension, and patients who self-assess their own blood pressure (BP) in the morning tend to exhibit better compliance with antihypertensive medication than those who do not.ObjectiveThe objective of this analysis was to determine the BP- and pulse rate-lowering effects of azelnidipine, a long-acting dihydropyridine calcium antagonist administered once daily in the morning.MethodsWe conducted the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study by surveying patients who were taking azelnidipine. According to the study protocol, high systolic BP (SBP) was defined as ≥135 mmHg when measured at home in the morning and ≥140 mmHg when measured at the clinic during the day. A total of 5,433 hypertensive patients, who were registered at 1,011 medical institutions across Japan, were enrolled in the study. Data obtained from 4,852 of these patients (mean age, 64.8 years; female, 52.9 %; previous medication with other antihypertensive agents used concomitantly with the present study agent, 45.5 %) were used for efficacy analysis.ResultsAt baseline, the subjects’ mean [± standard deviation] SBP/diastolic BP values at home in the morning, at the clinic during the day, and at home in the evening were 156.9 ± 16.4/89.7 ± 12.0, 157.5 ± 18.7/89.1 ± 13.3, and 150.2 ± 17.6/85.6 ± 12.2 mmHg, respectively. The mean pulse rates were 72.7 ± 10.7, 74.9 ± 11.2, and 72.5 ± 9.6 beats/min, respectively. Patients whose BP was defined as high accounted for 83.4 % of the study population, whereas 9.9 % had ‘masked’ hypertension, defined as SBP of ≥135 mmHg at home in the morning and <140 mmHg at the clinic. However, from 4 weeks after initiation of azelnidipine treatment till the end of the study at week 16, all three daily BP determinations were significantly (p < 0.0001) lowered, and pulse rates at home in the morning, at the clinic, and at home in the evening were similarly and significantly reduced (by −3.7 ± 8.0, −3.5 ± 9.5, and −3.5 ± 7.3 beats/min, respectively). Whereas achievement of home SBP of <135 mmHg in the morning was noted in only 6.6 % of patients before the start of azelnidipine treatment, this was noted in 43.3 % after 16 weeks. Meanwhile, achievement of clinic SBP of <140 mmHg was increased from 12.9 % of patients to 56.1 % of patients at the same timepoints. After azelnidipine treatment, 32.2 % of patients had well-controlled hypertension in both the home and clinic settings. Adverse drug reactions occurred in 2.92 % of patients (154/5,265). All adverse drug reactions were as expected for the calcium antagonist class of agents.ConclusionThese data suggest that azelnidipine controlled morning hypertension well. Furthermore, azelnidipine reduced pulse rates significantly.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-013-0006-8) contains supplementary material, which is available to authorized users.

Study of Sustained Blood Pressure-Lowering Effect of Azelnidipine Guided by Self-Measured Morning and Evening Home Blood Pressure: Subgroup Analysis of the At-HOME Study

BackgroundMorning hypertension is a risk factor for cardiovascular and cerebrovascular events, and consequently diagnosis and control of morning hypertension are considered very important. We previously reported the results of the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study, which indicated that azelnidipine effectively controlled morning hypertension.ObjectivesThe objective of this At-HOME subgroup analysis was to evaluate the sustained blood pressure (BP)-lowering effect of azelnidipine, using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference).MethodsWe analyzed the self-measured home BP data (measured in the morning and at bedtime) from this 16-week prospective observational study to clarify the effect of morning dosing of azelnidipine (mean [± standard deviation] maximum dose 14.3 ± 3.6 mg/day). A subgroup of patients from the At-HOME Study who had an evening home BP measurement within 28 days prior to the baseline date were used for efficacy analysis (n = 2,546; mean age, 65.1 years; female, 53.6 %).ResultsHome systolic BP/diastolic BP levels in the morning and evening were significantly lowered (p < 0.0001) by −19.4 ± 17.1/−10.3 ± 10.6 and −16.9 ± 17.0/−9.4 ± 10.6 mmHg, respectively. Home pulse rates in the morning and evening were also significantly lowered (p < 0.0001) by −3.5 ± 7.8 and −3.5 ± 7.3 beats/min, respectively. At baseline, patients whose ME average was ≥135 mmHg and whose ME difference was ≥15 mmHg (defined as morning-predominant hypertension) accounted for 20.4 % of the study population. However, at the end of the study, the number of such patients was significantly reduced to 7.9 % (p < 0.0001). Patients whose ME average was ≥135 mmHg and whose ME difference was <15 mmHg (defined as sustained hypertension) accounted for 71.1 % of the study population at baseline. This was reduced significantly to 42.8 % at the end of the study (p < 0.0001). ME average decreased significantly from 153.8 ± 15.5 mmHg to 135.6 ± 11.9 mmHg, and ME difference also decreased significantly from 6.7 ± 13.1 mmHg to 4.7 ± 10.8 mmHg (both p < 0.0001).ConclusionThese results suggest that azelnidipine improved morning hypertension with its sustained BP-lowering effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-013-0007-7) contains supplementary material, which is available to authorized users.

Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity

Dihydropyridine-type calcium channel blockers (CCBs) exert potent antihypertensive effects. The CCB azelnidipine decreases heart rate by suppressing sympathetic nerve activity, which affects afferent and efferent arterioles in the glomeruli. We examined whether azelnidipine can improve progressive glomerular injury in comparison with amlodipine by suppressing renal sympathetic nerve activity in Dahl salt-sensitive rats. Glomerular circulation in Dahl salt-sensitive rats was monitored with a charge-coupled device camera before and after administration of amlodipine (0.5 mg kg(-1), bolus injection) or azelnidipine (0.1 mg kg(-1), bolus injection). Systemic sympathetic nerve activity was also compared by analysis of heart rate variability with a telemetry blood pressure monitoring system after crossover administration of amlodipine (1.0 mg kg(-1) per day) and azelnidipine (3.0 mg kg(-1) per day) for 1 week. To investigate renoprotective effects, rats were treated with amlodipine (1.0 mg kg(-1) per day) or azelnidipine (3.0 mg kg(-1) per day) for 3 weeks with or without renal denervation. The efferent arteriole contracted in response to acute amlodipine but not azelnidipine treatment. The low frequency/high frequency ratio, an index of parasympathetic nerve activity, decreased in response to azelnidipine but not amlodipine treatment. In response to chronic treatment, proteinuria and glomerular injury improved to a greater extent with azelnidipine compared with amlodipine. The renoprotective effects of azelnidipine were diminished by renal denervation. Azelnidipine decreased glomerular damage in Dahl salt-sensitive rats to a greater extent than amlodipine. Azelnidipine appeared to decrease intraglomerular pressure by suppressing sympathetic nerve activity.

Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis

BackgroundNumerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition.MethodsThis study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence.ResultsDiabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment.ConclusionCollectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.

Calcium Channel Blocker Inhibition of AGE and RAGE Axis Limits Renal Injury in Nondiabetic Patients With Stage I or II Chronic Kidney Disease

There is a growing body of evidence that advanced glycation end products (AGE) and their receptor (RAGE) system are implicated in chronic kidney disease (CKD). We have previously found that a long-acting calcium channel blocker, azelnidipine, but not amlodipine, improves renal injury in CKD patients. However, little is known about the effect of azelnidipine on the AGE-RAGE axis in humans. In this study, we examined whether azelnidipine addition could have renoprotective properties in hypertensive CKD patients by reducing serum levels of AGE and soluble form of RAGE (sRAGE). Thirty nondiabetic stage I or II CKD patients who had already been treated with angiotensin II receptor blockers were enrolled in this study. We hypothesized that azelnidipine treatment could limit renal injury partly by blocking the AGE-RAGE axis. Patients were randomly divided into 2 groups; one group was treated with 16 mg azelnidipine and the other with 5 mg amlodipine once daily. They were followed up for 6 months. Proteinuria was positively correlated with circulating AGE and sRAGE levels in our subjects. Both drugs exhibited comparable and significant blood pressure (BP)-lowering effects. Although neither of them affected glucose, glycated hemoglobin, lipid levels, and estimated glomerular filtration rate, treatment with azelnidipine, but not amlodipine, decreased circulating AGE, sRAGE, proteinuria, and urinary levels of liver-type fatty acid binding protein, a marker of tubular injury, in a BP-lowering-independent manner. Our present results suggest that azelnidipine may exert renoprotective properties in nondiabetic hypertensive CKD patients via its unique inhibitory effects on the AGE-RAGE axis.

A New Baroreceptor Sensitivity-Restoring Ca-Channel Blocker Diminishes Age-Related Morning Blood Pressure Increase in Hypertensive Patients: Open-Label Monitoring of Azelnidipine Treatment for Hypertension in the Early Morning (At-HOME) Study.

Background: Morning blood pressure (BP) surge, which exhibits an age-related increase, is a risk factor for stroke in elderly hypertensive patients, independently of the 24-h BP level. We studied the effect of the new baroreceptor sensitivity (BRS)-restoring Ca-channel blocker (CCB) azelnidipine (AZ) on this age-related morning BP increase. Methods: We conducted a 16-week prospective study to clarify the effect of morning dosing of AZ on home BPs measured in the morning and in the evening in 2,546 hypertensive patients (mean age, 65.1 years; female, 53.6%). Results: At baseline, ME-Dif (morning systolic BP [SBP]–evening SBP) increased with age, independently of ME-Ave (average of the morning and evening SBPs). This age-related increase of ME-Dif was exaggerated by regular alcohol drinking and beta-blocker use. After AZ treatment (14.3 ± 3.6 mg/day), ME-AV and ME-Dif were significantly reduced independently of each other, with reductions of –18.1 ± 15.6 and –2.5 ± 13.2 mmHg, respectively (both p < 0.001). AZ treatment decreased age-related increase in ME-Dif particularly in patients who were regular consumers of alcohol and in beta-blocker users. Conclusions: The new BRS-restoring CCB AZ significantly reduced age-related increase in morning BP and had some potential benefit on cardiovascular protection in hypertension, particularly in elderly patients and/or consumers of alcohol.

Plasma Renin Activity and Aldosterone Concentration are not Altered by the Novel Calcium Channel Antagonist, Azelnidipine, in Hypertensive Patients

In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC. 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks. Azelnidipine treatment in drug-naïve (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values. These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

Impact of azelnidipine treatment on left ventricular diastolic performance in patients with hypertension and mild diastolic dysfunction: multi-center study with echocardiography

We investigated the impact of lowering blood pressure (BP) with azelnidipine, a newly developed calcium channel blocker, generation on the left ventricular (LV) diastolic function and LV filling pressure by assessing non-invasive indices derived from echo Doppler study. This study evaluated 232 hypertensive patients with diastolic dysfunction. This study had two groups: (1) in which azelnidipine was administered to patients as a first-line therapy, and (2) in which amlodipine was converted to azelnidipine. Early diastolic mitral annulus velocity (e', cm s(-1)), the ratio of peak E velocity to e' velocity (E/e' ratio) and level of brain natriuretic peptide (BNP) were measured before and, an average of, 8 months after azelnidipine treatment. In the first-line azelnidipine group, the systolic and diastolic BP reduced by 26 and 11 mm Hg, respectively. The e' increased, and E/e' ratio and BNP level decreased significantly. In the converted-from-amlodipine group, the systolic and diastolic BP decreased by 14 and 6 mmHg, respectively. The e' velocity increased, but the E/e' ratio and BNP level did not change. In both groups, azelnidipine lowered BP and improved LV diastolic function (an increase in the e' velocity). Possible reduction in LV filling pressure (a decrease in the E/e' ratio and BNP level) is observed only in the first-line azelnidipine group.

Beneficial Effects of Combination Therapy with Olmesartan and Azelnidipine in Murine Polycystic Kidneys

Background: Some reports have discussed the synergic effects of angiotensin II receptor blockers and calcium channel blockers on vascular injury or microalbuminuria. The present study examined the effects of combination treatment with olmesartan and azelnidipine on polycystic kidney disease in a mouse model (DBA/2-FG pcy mouse) and its mechanisms. Methods: The mice were divided into the following groups: combination treatment (n = 21), olmesartan treatment alone (n = 23), azelnidipine treatment alone (n = 29) or untreated (n = 26). Mean blood pressure and kidney weight were measured at 4 and 8 weeks after the treatment. Renal expression of angiotensin II, gp91, nitrotyrosine and endothelial NO synthase (eNOS) were examined by immunostaining. In addition, extracellular signal-regulated kinase activation was evaluated by Western blotting. Results: Olmesartan decreased the numbers of angiotensin II and gp91-positive cells, mainly macrophages, and cyst size at 4 weeks. However, only combination treatment suppressed cell infiltration, extracellular signal-regulated kinase activation and interstitial fibrosis with a significant change in the kidney weight/body weight ratio. The azelnidipine and combination treatment increased the numbers of interstitial eNOS-positive cells. Conclusion: The combination treatment protects against cyst enlargement in polycystic kidney disease by suppressing interstitial inflammation, fibrosis and oxidative stress by upregulating eNOS expression during disease course.

Azelnidipine Decreases Plasma Matrix Metalloproteinase-9 Levels after Endovascular Abdominal Aortic Aneurysm Repair

We investigated the changes of matrix metalloproteinase (MMP) -9 in the peripheral blood samples of patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs), and the effect of azelnidipine on plasma MMP-9 levels in those patients. Levels of MMP-9 were measured in 22 patients who underwent EVAR for AAAs, and results were compared between a group receiving 16 mg azelnidipine daily (n=12) and a control group without azelnidipine (n=10). Measurements were taken preoperatively, and at 1 month and 3 months, postoperatively. Patients without endoleaks after EVAR showed a significant decrease in mean plasma MMP-9 levels (preoperative value: 39.5+/-14.3 ng/mL, after 1 month: 25.0+/-12.6, after 3 months: 28.2+/-10.2 ng/mL; P=0.004). In contrast, no significant decreases in mean plasma MMP-9 levels were observed in the patients with endoleaks after EVAR (preoperative value: 37.5+/-9.0 ng/mL, after 1 month: 26.8+/-8.4, after 3 months: 38.5+/-15.7 ng/mL; P=0.219). Moreover, among patients without endoleaks, those receiving azelnidipine showed a significantly greater decrease in the mean plasma MMP-9 levels for 3 months postoperatively (preoperative value: 47.7+/-13.2 ng/mL, after 1 month: 26.6+/-12.8, after 3 months: 26.1+/-11.4 ng/mL; P0.001) compared with the control group without endoleaks (preoperative value: 31.3+/-10.5 ng/mL, after 1 month: 33.4+/-12.1, after 3 months: 30.3+/-9.1 ng/mL; P=0.792). These results showed that azelnidipine treatment in patients without endoleak after EVAR was associated with a significant decrease in mean plasma MMP-9 levels for 3 months postoperatively.