amlodipine Norvasc
Effects of the calcium channel blocker amlodipine on serum and aortic cholesterol, lipid peroxidation, antioxidant status and aortic histology in cholesterol-fed rabbits.

Turgan N, Habif S, Kabaroglu CG, Mutaf I, Ozmen D, Bayindir O, Uysal A.

Department of Clinical Biochemistry, Ege University School of Medicine, Izmir, Turkey. turgan med.ege.edu.tr

Reactive oxygen metabolites and oxidized fatty acids are proinflammatory and are involved in the pathophysiology of atherosclerosis. Amlodipine, a unique third-generation dihydropyridine-type calcium channel blocker, seems to exert atheroprotective effects through its antioxidant properties related to its chemical structure and independent of its calcium channel-blocking effect. In this study, the interactions of amlodipine with major cellular antioxidants were investigated in order to elucidate the mechanisms underlying its atheroprotective effects. New Zealand white male rabbits were fed regular chow (group 1), chow with 1% cholesterol (group 2), regular chow plus 5 mg/kg/day amlodipine per os (group 3) and 1% cholesterol plus amlodipine (group 4) for 8 weeks. Total cholesterol, malondialdehyde (MDA) and vitamin E concentrations and catalase and superoxide dismutase (SOD) activities were determined in blood drawn before and after the experimental period. Aortic tissue was examined for atherosclerotic changes and aortic total cholesterol, MDA, catalase and SOD were determined. At the end of the 8-week treatment period, serum total cholesterol and plasma MDA were elevated in groups 2 and 4. In group 2, serum vitamin E and plasma SOD diminished (p < 0.05) and catalase increased (p < 0.05). In group 4, SOD activity increased at the end of treatment. MDA levels were lower and plasma SOD activities were higher in group 4 than in group 2. Aortic tissue investigations revealed higher total cholesterol and MDA concentrations and catalase activities in group 2 than in group 4, and the highest tissue SOD activity was recorded in group 4 (p < 0.05 for all comparisons). Morphological examination of aortic tissues exhibited endothelial disarrangement and lipid deposition in group 2. Histopathological alterations related to atherogenesis were less in group 4 than in group 2. Amlodipine seems to exert atheroprotective effects by reducing aortic cholesterol accumulation and blood and aortic lipid peroxidation, enhancing SOD activity both in blood and aortic tissue and suppressing the consumption of vitamin E. On the other hand, the suppression of catalase activity in blood and the aorta interferes with the drug's well-known antioxidant effects. Copyright 2003 National Science Council, ROC and S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12566988&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Novel mechanisms of the antiproliferative effects of amlodipine in vascular smooth muscle cells from spontaneously hypertensive rats.

Lai YM, Fukuda N, Su JZ, Suzuki R, Ikeda Y, Takagi H, Tahira Y, Kanmatsuse K.

Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.

The calcium channel blocker amlodipine continues to be of interest due to its potential proven ability to hinder the progression of atherosclerosis and reduce the number of clinical ischemic events. Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) are useful in the study of atherosclerosis because they show exaggerated growth with production of angiotensin II (Ang II) by conversion to the synthetic phenotype. To clarify mechanisms of the antiproliferative effects of amlodipine, we evaluated effects of the expression of growth factors, the changes in phenotype, and the proliferation of VSMC from SHR. Amlodipine significantly inhibited basal DNA synthesis and proliferation of VSMC from SHR. Amlodipine also inhibited expression of platelet-derived growth factor (PDGF) A-chain, transforming growth factor beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) mRNAs in VSMC from SHR. Decreases in levels of PDGF A-chain and bFGF mRNAs in VSMC from SHR were greater with amlodipine than with nifedipine. Amlodipine significantly inhibited expression of the synthetic phenotype markers osteopontin and matrix Gla mRNAs, indicating that it inhibited the exaggerated growth of VSMC from SHR and suppressed the change from the contractile phenotype to the synthetic phenotype. Thus, amlodipine may be a beneficial therapeutic agent for patients with hypertensive vascular diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11924715&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vascular remodeling during healing after myocardial infarction in the dog model: effects of reperfusion, amlodipine and enalapril.

Jugdutt BI, Menon V, Kumar D, Idikio H.

Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. bjugdutt ualberta.ca

OBJECTIVES: We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ). BACKGROUND: The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined. METHODS: We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks. RESULTS: Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ. CONCLUSIONS: The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11985920&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Determination of Amlodipine in Pharmaceutical Formulations by Differential-Pulse Voltammetry with a Glassy Carbon Electrode.

Altiokka G, Dogrukol-Ak D, Tuncel M, Aboul-Enein HY.

Department of Analytical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey.

A differential-pulse voltammetric method was developed for the determination of amlodipine based on the oxidation of the dihydropyridine group on the surface of glassy carbon electrode under stationary and rotating conditions. The experiments were conducted in a supporting electrolyte consisting of 0.2 MKCl, 0.1 Mphosphate buffer, and 10 % (v/v) methanol during investigation of initial potential and pH effects. No adsorption effect was observed on using an initial potential of 0 mVand the supporting electrolyte solution at pH 5.5 under both stationary and rotating conditions. The factor affecting the voltammetric current was diffusional in the range of 200-1000 rpm for rotating, and 2-40 mV s(-1) for stationary conditions up to a concentration of 0.04 mg mL(-1) amlodipine. The limit of detection (LOD) and the limit of quantitative (LOQ) for the rotating and stationary techniques were found to be 0.004 and 0.0072 mg mL(-1) (for S/N = 3.3) and LOQ 0.012 and 0.022 mg mL(-1) (for S/N = 10), respectively. The proposed method was applied to the tablets containing amlodipine and according to the statistical evaluations acceptable results were obtained at the 95 % probability level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007115&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Reduced coronary vasodilator responses to amlodipine in pacing-induced heart failure in conscious dogs: role of nitric oxide.

Champagne S, Hittinger L, Heloire F, Suto Y, Sambin L, Crozatier B, Su JB.

INSERM U400, Faculte de Medecine, 94010 Creteil, France.

1. This study examined whether NO is involved in the in-vivo coronary vasodilator effects of amlodipine (a calcium channel blocker) and whether heart failure (HF) alters the coronary responses to amlodipine. 2. Nine conscious dogs were chronically instrumented to measure circumflex coronary blood flow (CBF) and coronary diameter (CD). Drugs were administered directly into the circumflex artery through an indwelling catheter to avoid systemic changes. HF was induced by right ventricular pacing (240 b.p.m., 3 weeks). 3. Compared with control (C), in HF, coronary responses to acetylcholine (1 - 10 ng kg(-1)) were reduced while responses to nitroglycerin (0.1 - 0.5 microg kg(-1)) were unchanged. In C, amlodipine (30 - 150 microg kg(-1)), increased dose-dependently CBF and CD. After LNA (a NO synthase inhibitor, 2 mg kg(-1)), amlodipine produced less increases in CBF and CD (+121+/-26 ml min(-1) and +76+/-35 microm versus +196+/-40 ml min(-1) and +153+/-39 microm respectively for 150 microg kg(-1) amlodipine alone, both P<0.05). In HF, the coronary responses to amlodipine were reduced (150 microg kg(-1) of amlodipine increased CBF and CD +121+/-23 ml min(-1) and +77+/-21 microm respectively, both P<0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94+/-19 ml min(-1) at 150 microg kg(-1)) but CD responses were significantly reduced (+41+/-16 microm, P<0.05). The supplementation with L-arginine did not enhance the coronary responses to amlodipine. 4. These results indicate that, in conscious dogs, NO participates in the coronary responses to amlodipine and in HF, the coronary responses to amlodipine are reduced, which is related to a reduced NO production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12010775&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine, but not verapamil or nifedipine, dilates rabbit femoral artery largely through a nitric oxide- and kinin-dependent mechanism.

Xu B, Xiao-hong L, Lin G, Queen L, Ferro A.

Department of Cardiology, Zhongda Hospital of Southeast University, Nanjing, People's Republic of China.

1. We investigated the nitric oxide (NO) dependence of vasorelaxation in response to different calcium channel blockers (CCB), in rabbit femoral artery in vivo. 2. Anaesthetized rabbits underwent femoral artery ligation, and blood from the proximal artery was returned distal to the ligature through a constant infusion pump. The effects of local injection of CCB on perfusion pressure and plasma nitrite+nitrate (NO(x), which reflects local NO biosynthesis) concentration in this system were determined. 3. Intra-arterial verapamil, nifedipine or amlodipine 10 micromol x kg(-1) each reduced perfusion pressure. Pre-treatment with intra-arterial N(G)-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) 1 micromol x kg(-1) did not affect responses to verapamil or nifedipine, but attenuated the reduction in perfusion pressure to amlodipine, from 33.2+/-2.1% to 22.5+/-1.6% (P=0.002). 4. Intra-arterial amlodipine--unlike verapamil or nifedipine--increased femoral venous NO(x), from 9.1+/-0.4 microM to 14.1+/-0.5 microM (P=0.005). 5. The bradykinin B2 receptor antagonist HOE 140, 30 mg x kg(-1), attenuated the reduction in perfusion pressure and abolished the rise in venous NO(x) concentration, following intra-arterial amlodipine. 6. Amlodipine potently inhibited serum angiotensin converting-enzyme (ACE) activity in vitro, as effectively as enalapril at similar concentrations. 7. These results suggest that the vasorelaxant effects of nifedipine and verapamil are NO-independent, whereas those of amlodipine are partly NO-dependent, in rabbit femoral artery in vivo. This effect of amlodipine occurs through B2 receptor activation, and may be related to an increase in local bradykinin through inhibition of ACE.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12023940&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Determination of amlodipine in pharmaceutical formulations by differential-pulse voltammetry with a glassy carbon electrode.

Altiokka G, Dogrukol-Ak D, Tuncel M, Aboul-Enein HY.

Department of Analytical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey.

A differential-pulse voltammetric method was developed for the determination of amlodipine based on the oxidation of the dihydropyridine group on the surface of glassy carbon electrode under stationary and rotating conditions. The experiments were conducted in a supporting electrolyte consisting of 0.2 M KCl, 0.1 M phosphate buffer, and 10% (v/v) methanol during investigation of initial potential and pH effects. No adsorption effect was observed on using an initial potential of 0 mV and the supporting electrolyte solution at pH 5.5 under both stationary and rotating conditions. The factor affecting the voltammetric current was diffusional in the range of 200-1000 rpm for rotating, and 2-40 mV s-1 for stationary conditions up to a concentration of 0.04 mg mL-1 amlodipine. The limit of detection (LOD) and the limit of quantitative (LOQ) for the rotating and stationary techniques were found to be 0.004 and 0.0072 mg mL-1 (for S/N = 3.3) and LOQ 0.012 and 0.022 mg mL-1 (for S/N = 10), respectively. The proposed method was applied to the tablets containing amlodipine and according to the statistical evaluations acceptable results were obtained at the 95% probability level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12043455&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency.

Mathur S, Syme H, Brown CA, Elliot J, Moore PA, Newell MA, Munday JS, Cartier LM, Sheldon SE, Brown SA.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30605, USA.

OBJECTIVE: To determine whether amlodipine besylate decreases systemic arterial blood pressure (BP) and reduces the prevalence of complications in cats with induced hypertensive renal insufficiency. ANIMALS: 20 cats with partial nephrectomy. PROCEDURE: Following reduction in renal mass, 10 cats were administered 0.25 mg of amlodipine/kg, PO, q 24 h (group A). Ten cats served as a control group (group C). Systolic BP (SBP), diastolic BP (DBP), and mean BP (MBP), physical activity, and pulse rate were measured continuously for 36 days by use of radiotelemetric devices. RESULTS: Compared with values for clinically normal cats, SBP, DBP, and MBP were significantly increased in cats of group C. Cats in group A had significant reductions in SBP, DBP, and MBP, compared with values for cats in group C. Albuminuria but not urine protein-to-creatinine ratio was significantly correlated (R2 = 0.317) with SBP in hypertensive cats. Prevalence of ocular lesions attributable to systemic hypertension in group C (7 cats) was greater than that observed in group A (2). Two cats in group C were euthanatized on day 16 because of nuerologic complications attributed to systemic hypertension. One normotensive cat in group A was euthanatized because of purulent enteritis of unknown cause on day 27. CONCLUSIONS AND CLINICAL RELEVANCE: Amlodipine had an antihypertensive effect in cats with coexistent systemic hypertension and renal insufficiency. Its use may improve the prognosis for cats with systemic hypertension by decreasing the risk of ocular injury or neurologic complications induced by high BP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12061529&dopt=Abstract amlodipine Norvasc