amlodipine Norvasc
Amlodipine inhibits pro-inflammatory cytokines and free radical production and inducible nitric oxide synthase expression in lipopolysaccharide/interferon-gamma-stimulated cultured vascular smooth muscle cells.

Chou TC, Yang SP, Pei D.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. tcchou ms5.hinet.net

Overproduction of nitric oxide (NO) from inducible nitric oxide synthase (iNOS) is importantly involved in the pathogenesis of endotoxemia and atherosclerosis. Calcium antagonists are commonly used as cardiovascular drugs and have a beneficial effect on prolonging survival in various models of endotoxin shock. The present study was to investigate the effect of a calcium antagonist amlodipine on nitrite, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) formation and iNOS induction both in lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-treated rat aortic smooth muscle cells (RASMC) and in a rat model of endotoxemia. Incubation with amlodipine (0.1 - 10 microM) for 24 h resulted in a significant and dose-dependent attenuation in medium nitrite, TNF-alpha and IL-1beta formation as well as iNOS protein expression in LPS/IFN-gamma-treated RASMC. In addition, amlodipine inhibited leucigenin-induced superoxide formation in RASMC. In the rat endotoxic model, the serum nitrite/nitrate, TNF-alpha and IL-1beta levels as well as iNOS protein expression of lungs were also suppressed by administration of amlodipine (50 microg/kg, i.v.). These results suggest that amlodipine may exert vascular beneficial effects by suppressing pro-inflammatory cytokines and free radical generation as well as iNOS induction in smooth muscle cells during activation of inflammatory mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12120758&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparative effects of telmisartan in the treatment of hypertension.

White WB.

Section of Hypertension and Clinical Pharmacology, University of Connecticut School of Medicine, Farmington, CT 06030-3940, USA.

Three separate randomized, double-blind, parallel-group, 12-week trials compared telmisartan with enalapril, lisinopril, and amlodipine for treating mild to moderate hypertension. Telmisartan 80 mg was associated with a significantly greater mean decrease in trough systolic and diastolic blood pressure than enalapril 20 mg (p<0.05). Mean decreases in trough systolic and diastolic blood pressure with telmisartan (40, 80, and 160 mg) and lisinopril (10, 20, and 40 mg) were similar. Telmisartan (40, 80, and 120 mg) provided greater decreases in mean hourly systolic and diastolic blood pressure throughout the 24-hour dosing interval, including the last 4 hours of the dosing period, than amlodipine (5 and 10 mg). Telmisartan was associated with a lower incidence of treatment-related cough than lisinopril and enalapril and less treatment-related angioedema than amlodipine. These data suggest that for treating mild to moderate hypertension, telmisartan has efficacy similar to lisinopril, greater efficacy than enalapril and amlodipine throughout the 24-hour dosing interval, and better tolerability than these angiotensin-converting enzyme inhibitors and amlodipine. Copyright 2002 Le Jacq Communications, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12147925&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Reduction of cerebral injury in stroke-prone spontaneously hypertensive rats by amlodipine.

Blezer E, Nicolay K, Goldschmeding R, Koomans H, Joles J.

Department of Nephrology and Hypertension (Room F03.226), University Medical Center, Heidelberglaan 100, P.O. Box 85500 3508 GA, Utrecht, The Netherlands.

Dihydropyridine Ca(2+) channel antagonists, initiated together with high salt intake, prevent the development of hypertension and subsequent cerebral damage in stroke-prone spontaneously hypertensive rats (SHRSP). We hypothesized that the dihydropyridine Ca(2+) channel antagonist amlodipine (approximately 15 mg/kg/day) could also reverse established hypertension and cerebral damage. SHRSP drank 1% NaCl from 8 weeks of age. Cerebral damage (cerebral edema and blood-brain barrier integrity) was investigated with magnetic resonance imaging twice a week. Systolic blood pressure was measured weekly. All rats developed severe hypertension and subsequent cerebral damage (defined as day 0). Untreated controls (n=7) died at day 12 (range: 7-28). Oral treatment with amlodipine (n=7), initiated at day 0, reduced systolic blood pressure, reversed cerebral edema and restored blood-brain barrier integrity. Systolic blood pressure remained low and eventually rats died after 450 days (range: 350-580) showing nephrosis but no recurrence of cerebral damage. In conclusion, established hypertension and cerebral damage are reversed by amlodipine in SHRSP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12191585&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure.

Grassi G, Spaziani D, Seravalle G, Bertinieri G, Dell'Oro R, Cuspidi C, Mancia G.

Cattedra di Medicina Interna, Universita di Milano, Ospedale S. Gerardo, Monza , Centro di Fisiologia Clinica e Ipertensione IRCCS, Ospedale Maggiore, Milano, Italy.

Short-acting calcium antagonists exert a sympathoexcitation that in heart failure further enhances an already elevated sympathetic activity. Whether this is also the case for long-acting formulations is not yet established, despite the prognostic importance of sympathetic activation in heart failure. It is also undetermined whether in this condition long-acting calcium antagonists favorably affect a mechanism potentially responsible for the sympathetic activation, ie, the baroreflex impairment. In 28 heart failure patients (NYHA functional class II) under conventional treatment we measured plasma norepinephrine and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during arterial baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at baseline and after 8 weeks of daily oral amlodipine administration (10 mg/d, 14 patients) or before and after an 8-week period without calcium antagonist administration (14 patients). Amlodipine caused a small and insignificant blood pressure reduction. Heart rate, left ventricular ejection fraction, and plasma renin and aldosterone concentrations were not affected. This was the case also for plasma norepinephrine (from 2.43+/-0.41 to 2.50+/-0.34 nmol/L, mean+/-SEM), muscle sympathetic nerve activity (from 54.4+/-5.9 to 51.0+/-4.3 bursts/min), and arterial baroreflex responses. No change in the above-mentioned variables was seen in the control group. Thus, in mild heart failure amlodipine treatment does not adversely affect sympathetic activity and baroreflex control of the heart and sympathetic tone. This implies that in this condition long-acting calcium antagonists can be administered without untoward neurohumoral effects anytime conventional treatment needs to be complemented by drugs causing additional vasodilatation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10024325&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Left ventricular mass regression with amlodipine in elderly hypertensives.

Singh NK, Gupta SK, Agrawal BV.

Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.

We evaluated effect of amlodipine therapy on left ventricular (LV) mass and function indices in 34 elderly hypertensives having echocardiographic evidence of left ventricular hypertrophy (LVH). LV mass and LV function indices were evaluated before and after 4 months of effective amlodipine therapy. Fourteen patients completed the study. Blood pressure was effectively controlled in all the patients; dose requirement of amlodipine being 5 mg/day in 8 and 10 mg/day in 6 patients. We found significant regression of LV mass indices such as thickness of interventricular septum (IVS) and left ventricular posterior wall (LVPW), and LV mass index after 4 months of amlodipine therapy. However, LV function indices did not alter following treatment. In conclusion, amlodipine therapy besides effectively controlling BP in elderly hypertensives, produced significant regression of LV mass indices without affecting the LV function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10052647&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine.

Mason RP, Walter MF, Trumbore MW, Olmstead EG Jr, Mason PE.

Department of Biochemistry, Cardiovascular and Pulmonary Research Institute, MCP-Hahnemann School of Medicine, Allegheny University of Health Sciences, Pittsburgh, PA 15212-4772, USA.

The effect of the highly lipophilic calcium channel antagonist (CCA) amlodipine on membrane oxyradical damage was examined and compared to that of other CCA analogs and a sulfhydryl-containing ACE inhibitor in isolated membrane vesicles enriched with polyunsaturated fatty acids (PUFA). Under physiological-like conditions, the dihydropyridine CCA amlodipine significantly (P<0.001) inhibited lipid peroxide formation (>10(2) microM) at concentrations as low as 10.0 nM. Under identical conditions, inhibition of lipid peroxide formation was not observed with representative CCA analogs (felodipine, verapamil, diltiazem) or the ACE inhibitor, captopril, at concentrations as high as 1.0 microM. The potent antioxidant activity of amlodipine is attributed to distinct membrane physico-chemical interactions. High-resolution differential scanning calorimetry showed that amlodipine effected marked changes in membrane thermodynamic properties as compared to other CCA analogs, including a marked reduction in the thermal phase transition temperature (-2.6 degrees C), enthalpy (-4.8 J/g) and cooperative unit size (-59%), relative to control samples. These findings indicate that the chemical structure of amlodipine contributes to distinct membrane biophysical interactions that lead to potent lipid antioxidant effects, independent of calcium channel modulation. These findings provide insights into potential new mechanisms of action for the charged CCA amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10072734&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells.

Mason RP, Leeds PR, Jacob RF, Hough CJ, Zhang KG, Mason PE, Chuang DM.

Cardiovascular and Pulmonary Research Institute, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212-4772, USA.

Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca2+ levels and inhibit cellular oxidative stress may be effective in blocking abnormal neuronal apoptosis. In this study, a spontaneous (also referred to as age-induced) model of apoptosis consisting of rat cerebellar granule cells was used to evaluate the antiapoptotic activities of voltage-sensitive Ca2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10-100 nM), amlodipine attenuated intracellular neuronal Ca2+ increases elicited by KCl depolarization but did not affect Ca2+ changes triggered by N-methyl-D-aspartate receptor activation. Amlodipine also inhibited free radical-induced damage to lipid constituents of the membrane in a dose-dependent manner, independent of Ca2+ channel modulation. In parallel experiments, spontaneous neuronal apoptosis was inhibited in dose- and time-dependent manners by antioxidants (U-78439G, alpha-tocopherol, and melatonin), nitric oxide synthase inhibitors (N-nitro-L-arginine and N-nitro-D-arginine), and a nitric oxide chelator (hemoglobin) in the micromolar range. These results suggest that spontaneous neuronal apoptosis is associated with excessive Ca2+ influx, leading to further intracellular Ca2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage-sensitive Ca2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10098848&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Beneficial effect of myocardial angiogenesis on cardiac remodeling process by amlodipine and MCI-154.

Kumamoto H, Okamoto H, Watanabe M, Onozuka H, Yoneya K, Nakagawa I, Chiba S, Watanabe S, Mikami T, Abe K, Kitabatake A.

Department of Cardiovascular Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan. hkumamo med.hokudai.ac.jp

The present study examined the effect of long-term treatment with amlodipine and MCI-154 (a Ca2+ sensitizer) on progressive cardiac dysfunction and microvasculature in the dilated cardiomyopathic (DCM) hamster heart. After treatment of DCM hamsters (Bio 53.58) with amlodipine or MCI-154 for 15 wk from the age of 5 wk, amlodipine and MCI-154 were found to cause an increase in left ventricular percent fractional shortening and decreases in left ventricular diastolic dimension and isovolumic relaxation time in echocardiograms (P < 0.01). A hemodynamic study showed that the diastolic time constant decreased in the amlodipine-treatment group (P < 0.05). In a morphometric study employing a double-staining method that discriminated arteriolar and venular capillaries, amlodipine and MCI-154 caused increases in total capillary density (P < 0.05) and the proportion of venular capillaries (P < 0.05). Moreover, Northern blot analysis showed that the expression of mRNA for vascular endothelial growth factor was significantly increased by amlodipine and MCI-154. They preserve coronary microvasculature in the DCM hamster and might induce angiogenesis of small vessels, thereby contributing to preservation of cardiac systolic and diastolic function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10199832&dopt=Abstract amlodipine Norvasc