Disease relevance of D01145

• Similar effects of azelnidipine were substantiated in an in vivo ischemia/reperfusion injury model [1].
• Among 172 patients with uncontrolled hypertension receiving non-calcium channel antagonist antihypertensive agents, the addition of azelnidipine therapy significantly reduced mean BP in a noncomparative, 1-year study (a reduction from 165.7/95.4 mm Hg at baseline to 138.2/79.9 mm Hg at study end) [2].
• Such inhibitory effects of azelnidipine on brain ischemia could be observed in AT1a receptor-deficient mice [3].
• RESULTS: Azelnidipine suppressed cardiac hypertrophy, fibrosis, NADPH oxidase and superoxide in spSHRs more potently than amlodipine, and was associated with lower heart rates than amlodipine [4].
• The lack of both tachycardia and increase of PRA is probably mostly due to the slow onset of antihypertensive action following CS-905 [5].

High impact information on D01145

• Azelnidipine administration ameliorated cellular and mitochondrial Ca(2+) accumulation, mitochondrial permeability transition, cytochrome c release, caspase-9 activation, and resultant apoptosis (15.8 +/- 0.8% versus 8.9 +/- 0.7%; P < 0.01) [1].
• Interestingly, azelnidipine increased rather than decreased the later ERK peaks in cells treated with small interfering RNA against mitogen-activated protein kinase phosphatase-1 [6].
• The calcium channel blocker azelnidipine attenuated the later peaks of extracellular signal-regulated kinase (ERK), tyrosine kinase 2, Jak2 activation, and phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 [6].
• Moreover, azelnidipine synergistically enhanced the inhibitory action of olmesartan on brain ischemia, suggesting beneficial combined effects of a CCB with an AT1 receptor blocker on ischemic brain damage [3].
• A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates [7].

Chemical compound and disease context of D01145

• Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension [2].
• An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration [8].

Biological context of D01145

• Azelnidipine, without causing an increase in heart rate, has the potential to be useful for the treatment of cardiac remodelling [4].
• Results from clinical trials showed that, in 95 patients with mild-to-moderate hypertension, long-term treatment with azelnidipine effectively controls blood pressure (BP) [2].
• CONCLUSION: These results indicate that azelnidipine inhibited ischemic brain damage induced by MCA occlusion, at least in part, through suppression of blood flow change and oxidative stress via a signaling mechanism independent of AT1 receptor stimulation [3].
• These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance [9].
• Continuous intrarenal infusion of CS-905 in anesthetized normotensive Munich Wistar rats at doses that did not affect MAP caused a marked diuresis and natriuresis, without affecting RPF or GFR [10].

Anatomical context of D01145

• Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro [7].
• CONCLUSIONS: This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima [7].
• Azelnidipine caused a greater reduction than amlodipine in the beat rate of the sinus node/atrial preparation of spSHRs [4].
• Treatment with azelnidipine (5 microg/kg/min i.v., 10 min) had no effect on basal MAP, RBF, RVR, or PTC erythrocyte velocity [11].
• Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle [9].

Associations of D01145 with other chemical compounds

• Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice [12].
• METHOD: Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each) [7].
• Furthermore, we observed similar inhibitory effects of azelnidipine or olmesartan on angiotensin II-induced NADPH oxidase activity and Akt activity in cultured vascular smooth muscle cells [12].
• The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba(2+) currents in guinea-pig vascular smooth muscle [13].
• The scavenging activities of azelnidipine against superoxide, hydroxyl, and carbon-centered radicals were determined by electron spin resonance assay [14].

Gene context of D01145

• Azelnidipine also completely prevented TNF-alpha-induced increase in NADPH oxidase activity in HUVEC [15].
• In this study, we investigated whether and how azelnidipine, a newly developed long-acting calcium antagonist, could inhibit TNF-alpha-induced IL-8 expression in human umbilical vein endothelial cells (HUVEC) [15].
• Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it [9].
• Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension [16].
• Azelnidipine significantly inhibited the expression of protein and mRNA of VCAM-1, and prevented the U937 cell adhesion to endothelial cells treated with 7-ketocholesterol or TNF-alpha [14].

Analytical, diagnostic and therapeutic context of D01145

• To determine whether the diuretic and natriuretic effects of CS-905 were mediated by changes in inner medullary blood flow, the effect of CS-905 on vasa recta blood flow (Qvr) was studied by fluorescent videomicroscopy in anesthetized normotensive Munich Wistar rats during continuous intrarenal infusion [10].
• Western blotting analysis revealed that activation of protein kinase C (PKC)alpha was inhibited by azelnidipine treatment, while it also reduced the SDF-1-induced increase in intracellular calcium concentration ([Ca(2+)](i)) [17].
• On a single oral administration in 38 week-old SHR, CS-905 caused natriuresis at a dose of 3 mg/kg, but did not affect urinary protein excretion and urinary NAG activity [18].
• The newly developed calcium antagonist, azelnidipine, increases drain volume in continuous ambulatory peritoneal dialysis patients [19].
• In the isolated arteries, the calcium blocking action developed gradually after treatment with azelnidipine and survived for a long period of time after the drug was removed from the bathing solution [20].

References