Background: The endothelium modulates vascular tone by synthesizing and releasing several vasodilating factors, including vasodilator prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In the present study, we examined whether an angiotensin-receptor blocker, a calcium-channel blocker or their combination improved EDHF-mediated responses in diabetic apolipoprotein E-deficient (ApoE(-/-)) mice. Methods and Results: We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE(-/-) mice. The diabetic ApoE(-/-) mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mg.kg(-1).day(-1)), azelnidipine (AZL, 10 mg.kg(-1).day(-1)), their combination (OLM + AZL), or hydralazine (HYD 5 mg.kg(-1).day(-1)) for 5 weeks. In the untreated group, systolic blood pressure was significantly higher and both EDHF-mediated relaxation and endothelium-dependent hyperpolarization were markedly reduced as compared with the control group. Although EDHF-mediated relaxation was not significantly improved in the HYD, OLM and AZL groups, it was significantly improved in the OLM + AZL group, as was also the case with phosphorylation of Akt and endothelial NO synthase (eNOS). In contrast, the endothelium-independent relaxation response to sodium nitroprusside or NS-1619 (a direct opener of K(Ca) channels) was unaltered in any group. Conclusions: OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE(-/-) mice, in which activation of the endothelial Akt - eNOS pathway may be involved.

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.

Calcium channel blockers are widely used for the treatment of hypertension. Although they are effective for their strong vasodilator action, there are concerns regarding related baroreflex-mediated activation of sympathetic nervous system. However, long-acting calcium channel blockers, such as amlodipine, are now known safe for the treatment of hypertension. Furthermore, the new type of calcium channel blockers, such as cilnidipine with N-type calcium channel blocking action, or azelnidipine that has sympatho-inhibitory action with anti-oxidant effect, provide a new insight for the future use of calcium channel blockers.

Text book in all medical school showed that the baroreflex system is one of the most important regulatory systems. When blood pressure increases, heart rate decrease and an artery is dilated with the baroreflex system. By decrease of cardiac output and arterial resistances, blood pressure returns to the normal value. However, there is no diagnostic method, which can measure the sensitivity of a baroreflex system of the artery by the simple methodology. We had challenged invention of the new machine, which could diagnose the sensitivity of the baroreflex system of not only a heart, but also an artery. In this system, the measurement sections are only an electrocardiography (ECG) and peripheral pulse wave. These time series is inputted into a personal computer system, and analyzed quantitatively. Responses of the artery were measured with pulse wave velocity (PWV) calculated from pulse wave transmission time from heart to an artery. In this system, the heart rate change corresponding to the blood-pressure change in time series sequence is observed. Delay time was measured by the cross correlation function. Slope of the blood pressure (BP) change and heart rate (HR) change showed the sensitivity of the baroreflex system of heart. Furthermore, this system can measure the sensitivity of the baroreflex system of an artery. Change of PWV in response to the BP change was observed. We found that significant correlation was observed in the time sequence between BP change and PWV change after delay time calculated from cross correlation. Clinical research was started through allowance of the Ethics Committee. Decreased sensibility in the hypertensive patient's baroreflex system was observed as a result of the clinical research. Furthermore, alteration of the baroreflex sensitivity before and after the drug administration was evaluated. For example, Azelnidipine, Calcium antagonists improved the baroreflex sensitivity of the artery in several cases. This system may be useful f- or the follow up of the hypertensive patients.

AAV1/SERCA2a, Abacavir sulfate/lamivudine, Adalimumab, Aliskiren fumarate, Ambrisentan, Aripiprazole, AT-7519, Atazanavir sulfate, Atomoxetine hydrochloride, Azacitidine, Azelnidipine; Besifloxacin hydrochloride, Bevacizumab, Bioabsorbable everolimus-eluting coronary stent, Bortezomib, Bosentan, Budesonide/formoterol fumarate; CAIV-T, Carisbamate, Casopitant mesylate, Certolizumab pegol, Cetuximab, Ciclesonide, Ciprofloxacin/dexamethasone, CTCE-9908; Dalcetrapib, Darunavir, Deferasirox, Desloratadine, Disitertide, Drotrecogin alfa (activated), DTA-H19, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Efalizumab, Emtricitabine, Eribulin mesilate, Escitalopram oxalate, Eszopiclone, EUR-1008, Everolimus-eluting coronary stent, Exenatide; Fampridine, Fluticasone furoate, Formoterol fumarate/fluticasone propionate, Fosamprenavir calcium, Fulvestrant; Gabapentin enacarbil, GS-7904L; HPV-6/11/16/18, Human Secretin, Hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, Imexon, Inalimarev/Falimarev, Indacaterol, Indacaterol maleate, Inhalable human insulin, Insulin detemir, Insulin glargine, Ixabepilone; L-Alanosine, Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Loratadine/montelukast sodium, Lutropin alfa; MeNZB, Mepolizumab, Micafungin sodium, Morphine hydrochloride; Nabiximols, Nikkomycin Z; Olmesartan medoxomil, Omalizumab; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Perifosine, PF-489791, Plitidepsin, Posaconazole, Pregabalin; QAX-576; Raltegravir potassium, Ramelteon, Rasagiline mesilate, Recombinant human relaxin H2, rhGAD65, Rivaroxaban, Rosuvastatin calcium, Rotigotine; Saxagliptin, SCH-530348, Sirolimus-eluting stent, SLIT-amikacin, Sorafenib, Sotrastaurin, SR-16234, Sulforaphane; Tadalafil, Tanespimycin, Tapentadol hydrochloride, Teriparatide, Tesofensine, Tiotropium bromide, Tipifarnib, Tirapazamine, TMC-207, Tocilizumab, Tolvaptan, Tosedostat, Treprostinil sodium; Ustekinumab; Varespladib methyl, Vicriviroc, Vildagliptin, Vildagliptin/metformin hydrochloride, Volociximab, Voriconazole; Ziconotide, Ziprasidone hydrochloride.

Azelnidipine is a new dihydropyridine Ca(2+) channel blocker with long plasma half-life. To understand the in vivo cardiovascular profile of azelnidipine, it was assessed in the halothane-anaesthetized, closed-chest canine model and compared with the effect of amlodipine. We administered azelnidipine in doses of 10, 20 and 70 mug/kg, i.v. or amlodipine in doses of 30, 70 and 200 mug/kg, i.v. cumulatively to the animals. The hypotensive effects of azelnidipine and amlodipine were slow in onset and long-lasted, while their extents of dose-related hypotensive effects were similar. Azelnidipine hardly affected the heart rate or plasma noradrenaline concentration at any doses, whereas the high dose of amlodipine increased these parameters. Azelnidipine as well as amlodipine tended to increase the ventricular contraction, which did not achieve statistical significance. During autonomic receptor blockade with atropine and propranolol, neither drug affected the heart rate, ventricular contraction or plasma noradrenaline concentration, although a more significant hypotensive action was observed. These results indicate that azelnidipine and amlodipine do not directly affect cardiac function. Amlodipine may induce sinus tachycardia via reflex-mediated increase in sympathetic tone. Such lack of reflex tachycardia with azelnidipine will provide potential therapeutic strategy for treatment of patients with cardiovascular diseases, being more beneficial than amlodipine.

Azelnidipine, a long-acting calcium channel blocker, is highly lipid soluble and selective for the vascular wall, and is expected to have an increasing effect on cerebral blood flow (CBF). The aim of this study is to investigate its safety and efficacy in stroke patients in the chronic stage as far as CBF is concerned using N-isopropyl-p-(123)I-iodo amphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). The patients were orally administered 8 or 16 mg of azelnidipine. Regional CBF was evaluated by (123)I-IMP SPECT using three-dimensional stereotactic region-of-interest (ROI) template (3D-SRT), a technique using anatomical standardization and ROI template consisting of 636 ROIs for the whole brain. Mean hemispheric CBF was defined as the mean value of the corpus callosum, and the precentral, central, parietal, angular and temporal gyri. Mean hemispheric and regional CBF after 1, 3 and 6 months were analyzed using a one-way repeated-measures analysis of variance. Ten post-ischemic stroke patients with hypertension were enrolled between October 2005 and October 2007, and all of them were well controlled with normal blood pressure (before: 172.3+/-16.6/88.4+/-14.0 mm Hg; 6 months: 128.7+/-15.9/70.9+/-10.1 mm Hg). No vascular events were observed during the study period. The mean hemispheric CBF was maintained during the study period (before: 46.0+/-9.7 ml per 100 g per min; 6 months: 49.3+/-11.1 ml per 100 g per min). The regional CBF was also maintained. In the chronic stage of ischemic stroke, azelnidipine could safely decrease systemic blood pressure without decreasing CBF.Hypertension Research advance online publication, 30 October 2009; doi:10.1038/hr.2009.179.

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.Hypertension Research advance online publication, 9 October 2009; doi:10.1038/hr.2009.163.

PURPOSE: Many trials have shown that calcium channel blockers (CCBs) can reduce the cardiovascular (CV) events in patients with coronary artery disease (CAD). The mechanisms of this effect could be associated with plaque regression due to the anti-atherosclerotic properties of CCBs. The goal of this study is to determine the effects of CCB on volumetric quantitative changes of coronary plaques accessed by intravascular ultrasound (IVUS). To confirm this hypothesis, a multicenter randomized trial of CCBs treatment with azelnidipine or amlodipine will be conducted in hypertensive CAD patients undergoing elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients who have hypertension and are scheduled for PCI will be enrolled. Subjects will be randomized to azelnidipine or amlodipine and observed for 48 weeks. The primary endpoint will be the percent change of coronary plaque volume. The secondary endpoint will include inflammatory markers, antioxidant activity, and incidence of composite cardiovascular events. CONCLUSIONS: In this study, we will investigate the improvement of coronary plaque with IVUS by treatment with two dihydropyridine CCBs in hypertensive patients undergoing elective PCI. This result will lead to the discovery of more effective drug therapy for inhibition of coronary events.

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.

SUMMARY: The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E(max)) of olmesartan, whereas azelnidpine E(max) was independent of patient background characteristics investigated. No patient was found to have a high E(max) to one agent who also had a high E(max) to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

BACKGROUND: We assessed the renal protective effects of treatment with moderate exercise (EX), with EX plus olmesartan (OLS), with EX plus azelnidipine (AZN), and with the three together in a rat model of chronic renal failure (CRF). METHODS: Male 5/6-nephrectomized Wistar Kyoto (WKY) rats were divided into six groups according to the following treatments for: (i) no EX (C); (ii) moderate EX with treadmill running (20 m/min for 60 min/day, 5 days/week) (EX); (iii) EX+OLS (10 mg/kg/day); (iv) EX+AZN (3 mg/kg/day); (v) EX+OLS (5 mg/kg/day)+AZN (1.5 mg/kg/day); and (vi) sham operation (S). The rats were then treated for 12 weeks. RESULTS: EX, EX+OLS, EX+AZN, and EX+OLS+AZN showed decreases in the serum creatinine (Scr), an index of glomerular sclerosis (IGS), the relative interstitial volume of the renal cortex (RIV), the number of ED-1 (monoclonal antibody) positive cells (ED1(+)) and the glomerular expression score of alpha-smooth muscle actin (alpha-SMA(+)). EX+OLS, EX+AZN, and EX+OLS+AZN blocked the development of hypertension, increased the number of Wilms' tumor-1 (WT-1) positive cells (WT1(+)); EX+OLS and EX+OLS+AZN blunted the increases in proteinuria. In particular, blood urea nitrogen (BUN), ED1(+), alpha-SMA(+), WT1(+), IGS, and RIV in the EX+OLS+AZN were the lowest among all the nephrectomized groups. CONCLUSIONS: In the results, simultaneous treatment of EX, OLS, and AZN showed renal protective effects in this rat model suggesting that the treatment may affect the macrophage infiltration to the glomerulus, the fibroblast accumulation in the glomerulus, the mesangial activation, and the podocyte differentiation.

To achieve the target blood pressure recommended by the latest guidelines, multiple antihypertensive drugs are needed in most patients. In this study, the efficacy of treatment using an angiotensin II receptor antagonist (ARB) combined with a calcium channel blocker (CCB) or a diuretic was compared from multiple perspectives in patients with hypertension. Twenty-nine patients with essential hypertension, who had failed to achieve their target blood pressure (<130/85 mm Hg for patients <65 years old and <140/90 mm Hg for those >/=65 years) when treated with the ARB olmesartan at 20 mg day(-1), were additionally given 8-16 mg day(-1) of the CCB azelnidipine or 1-2 mg day(-1) of trichlormethiazide (a thiazide diuretic) in a randomized crossover manner for 4 months each. At the end of each combination therapy period, blood and urine samples were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity. Compared with monotherapy, the blood pressure was reduced similarly by adding azelnidipine (-12/-10 mm Hg) or trichlormethiazide (-14/-9 mm Hg). The heart rate was decreased with the CCB by 4 b.p.m. (P<0.05), whereas it was unchanged with the thiazide. Serum K, lipids and blood glucose were not significantly changed with either combination, whereas serum uric acid was increased with the thiazide (P<0.01) but was unchanged with azelnidipine. Plasma levels of renin, angiotensin II and aldosterone were also increased with the thiazide period, whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine. In addition, the cardio-ankle vascular index, a parameter of arterial stiffness, was decreased with the azelnidipine period but was unchanged with the thiazide period (P<0.01). It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia, sympathetic activation, renin-angiotensin-aldosterone system stimulation, inflammation, oxidative stress, and increased arterial stiffness in patients with moderate hypertension. These properties may provide cardiovascular protection in addition to the hypotensive effect.Hypertension Research advance online publication, 21 August 2009; doi:10.1038/hr.2009.133.

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.

The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (n=103) or hydrochlorothiazide (n=104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P=0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: -2.2 to 7.5 mm Hg; P=0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; P<0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan (20.0 mg) and azelnidipine (16.0 mg) had a more beneficial effect on central systolic BP and arterial stiffness than the combination of olmesartan (20.0 mg) and hydrochlorothiazide (12.5 mg), despite the lack of a significant difference in brachial systolic BP reduction between the 2 treatments.

BACKGROUND: Hypoxia-induced tubulointerstitial injury caused by loss of peritubular capillary (PTC) blood flow may be associated with progressive renal disease. Therefore, the maintenance of blood flow in PTCs may protect against loss of renal function. A long-acting calcium channel blocker, azelnidipine, has been shown to be useful in the treatment of progressive renal disease. However, its mechanism of action remains unclear. The aim of the present study was to elucidate whether azelnidipine maintains PTC blood flow and to compare it to nifedipine in its ability to improve tubulointerstitial injury caused by angiotensin II (AII) infusion in rats. METHODS: PTC blood flow was initially monitored using a pencil-lens interval microscope before and after intravenous AII (30 ng/kg/min) infusion with or without azelnidipine (10 mug/kg/min). Next, Wistar rats were treated with chronic infusion of AII (500 ng/kg/min) via an osmotic minipump with or without azelnidipine (3 mg/kg/day, orally) or nifedipine (60 mg/kg/day, orally) for 14 days, and tubulointerstitial damage (PTC loss, interstitial fibrosis, tubular atrophy) was examined. RESULTS: PTC blood flow was reduced after AII infusion but improved after a bolus injection of azelnidipine. Tubulointerstitial damage observed in chronically AII-treated kidneys was associated with hypoxic conditions, as indicated by the measurement of hypoxia biomarkers (intracellular hypoxyprobe-1 adducts). These tubulointerstitial injuries in AII-infused rats were more effectively reduced by azelnidipine than by nifedipine. The area showing hypoxic conditions in the kidney was also more reduced with azelnidipine than nifedipine treatment. CONCLUSIONS: Azelnidipine may increase PTC blood flow and improve renal hypoxia and tubulointerstitial injury induced by AII infusion.

(+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan.

Currently, a new type of calcium channel blockers, which can inhibit not only L-type calcium channels abundantly expressed in vascular smooth muscles, but also N-type calcium channels that abound in the sympathetic nerve endings, have been developed. In this study, analysis on a like-for-like basis of the L- and N-type calcium channel-inhibitory activity of typical dihydropyridine-type calcium-channel blockers (DHPs) was performed. Moreover, to understand the differences of N-type calcium channel inhibition among DHPs, the binding of DHPs to the channel was investigated by means of hypothetical three-dimensional pharmacophore modeling using multiple calculated low-energy conformers of the DHPs. All of the tested compounds, i.e. cilnidipine (CAS 132203-70-4), efonidipine (CAS 111011-76-8), amlodipine (CAS 111470-99-6), benidipine (CAS 85387-35-5), azelnidipine (CAS 123524-52-7) and nifedipine (CAS 21829-25-4), potently inhibited the L-type calcium channel, whereas only cilnidipine inhibited the N-type calcium channel (IC50 value: 51.2 nM). A virtual three-dimensional structure of the N-type calcium channel was generated by using the structure of the peptide omega-conotoxin GVIA, a standard inhibitor of the channel, and cilnidipine was found to fit well into this pharmacophore model. Lipophilic potential maps of omega-conotoxin GVIA and cilnidipine supported this finding. Conformational overlay of cilnidipine and the other DHPs indicated that amlodipine and nifedipine were not compatible with the pharmacophore model because they did not contain an aromatic ring that was functionally equivalent to Tyr13 of omega-conotoxin GVIA. Azelnidipine, benidipine, and efonidipine, which have this type of aromatic ring, were not positively identified due to intrusions into the excluded volume. Estimation of virtual three-dimensional structures of proteins, such as ion channels, by using standard substrates and/or inhibitors may be a useful method to explore the mechanisms of pharmacological and toxicological effects of substrates and/or inhibitors, and to discover new drugs.

OBJECTIVES: Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury. METHODS AND RESULTS: Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 microg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22 and gp91). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22 and gp91, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells. CONCLUSION: These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.