Prevention of vascular injury by combination of an AT1 receptor blocker, olmesartan, with various calcium antagonists.
ABSTRACT A combination of different types of antihypertensive drugs is widely used for the treatment of hypertension. We examined the inhibitory effects of a combination of an AT(1) receptor blocker (ARB), olmesartan, with various calcium channel blockers (CCBs) on inflammatory vascular remodeling.
Inflammatory vascular remodeling was induced by polyethylene-cuff placement around the femoral artery of C57BL/6J mice at 10 weeks of age. Olmesartan (0.5 mg/kg/day) was administered intraperitoneally using an osmotic minipump. CCBs (nifedipine 1.0 mg/kg/day, amlodipine 0.1 mg/kg/day, azelnidipine 0.1 mg/kg/day), and hydrochlorothiazide (HCTZ 0.5 mg/kg/day) were administered orally.
In the injured artery, superoxide anion production and expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47(phox) and Rac-1 were markedly increased, together with expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-alpha. Administration of a single drug alone at each concentration did not significantly inhibit these changes in the injured artery. However, a combination of olmesartan with various CCBs inhibited neointimal formation as well as oxidative stress and inflammatory markers in the injured artery. Moreover, among these CCBs, inhibition of these markers by olmesartan with azelnidipine was stronger than that caused by a combination with other CCBs. On the other hand, a combination of subeffective doses of olmesartan and HCTZ did not significantly affect vascular changes after cuff placement.
These results suggest that the combination of ARB with CCB synergistically inhibits vascular remodeling and that the inhibitory actions of ARB on vascular remodeling may vary depending on the combined CCB.
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ABSTRACT: The dihydropyridine calcium channel blocker nifedipine induces specific pharmacological effects by binding to L-type calcium channels, which results in a reduced calcium influx in vascular smooth muscle cells (VSMCs) and is currently employed in antihypertensive drug. Dihydropyridine calcium channel blocker is reported to reduce oxidative stress and exhibits anti-proliferative effect in VSMCs. VSMCs are useful in the study of atherosclerosis because they show cell proliferation and reactive oxygen species (ROS) production with growth factor. To determine the mechanisms involved in these effects, we investigated the influence of nifedipine-induced AMP-activated protein kinase (AMPK) activation on VSMC proliferation and ROS production by using rat aortic VSMCs in vitro and in vivo. Nifedipine induced phosphorylation of AMPK in a dose-and time-dependent manner, and inhibited rat VSMC proliferation and ROS production following stimulation with 15% fetal bovine serum (FBS). Nifedipine also blocked the FBS-stimulated cell cycle progression through the G0/G1 arrest. Compound C, a specific inhibitor of AMPK, or AMPK siRNA reduced the nifedipine-mediated inhibition of VSMC proliferation. As an upstream kinase, LKB1 is required for nifedipine-induced AMPK activation in VSMCs. 7 days oral administration of 1 mg/kg nifedipine resulted in activation of LKB1 and AMPK in vivo. These data suggest that nifedipine suppress the VSMC proliferation and ROS production via activating LKB1-AMPK pathway.Vascular Pharmacology 06/2011; 56(1-2):1-8. · 3.21 Impact Factor
Article: Design and rationale of Japanese evaluation between Formula of Azelnidipine and amlodipine add on olmesartan to Get antialbuminuric effect study (J-FLAG) : evaluation of the antialbuminuric effects between calcium channel blocker with sympatholytic action in hypertensive patients with diabetes and albuminuria.[Show abstract] [Hide abstract]
ABSTRACT: Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine. A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8-16 mg/day) and amlodipine (2.5-5 mg/day) in olmesartan-treated hypertensive (blood pressure 130-180/80-110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment. The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy.Cardiovascular Drugs and Therapy 06/2011; 25(4):341-7. · 2.67 Impact Factor
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ABSTRACT: Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.Hypertension Research advance online publication, 29 November 2012; doi:10.1038/hr.2012.187.Hypertension Research 11/2012; · 2.79 Impact Factor