amlodipine Norvasc
Vasodilatory action of the calcium antagonist amlodipine on large and resistance pulmonary arteries from normoxic and chronically hypoxic rats.

Woodmansey PA, Zhang F, Channer KS, Morice AH.

University Department of Medicine, Royal Hallamshire Hospital, Sheffield, U.K.

1. Isolated rat aorta and pulmonary arteries were maximally precontracted with 100 mmol/l KCl, and the vasorelaxation due to the dihydropyridine calcium antagonist amlodipine was measured. The response of large pulmonary arteries (mean lumen diameter 983 microns) was directly compared with that of isolated pulmonary resistance vessels (mean lumen diameter 259 microns) from both normoxic animals and animals exposed to chronic hypoxia. 2. Amlodipine caused a significant relaxation of aorta (P < 0.001). A significant relaxation of large and resistance pulmonary arteries from both normoxic and chronically hypoxic animals was also demonstrated at all doses tested (P < 0.05) or less). 3. Amlodipine produced significantly more relaxation in pulmonary resistance vessels than in large pulmonary arteries from both normoxic and chronically hypoxic rats (P < 0.02). 4. The action of amlodipine was slow in onset and persistent in all vessels studied. In the pulmonary vessels from normoxic animals both the rate of onset and the magnitude of effect was proportional to the drug concentration (P < 0.001). 5. These results demonstrate that amlodipine is a potent inhibitor of KCl-induced contractions in rat pulmonary arteries with a preferential action in pulmonary resistance vessels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8403809&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Long term effects of amlodipine on organ damage, stroke and life span in stroke prone spontaneously hypertensive rats.

Suzuki M, Yamanaka K, Nabata H, Tachibana M.

Pharmacology Laboratory, Pfizer Pharmaceuticals Inc., Aichi, Japan.

The long term effects of amlodipine, a new long acting Ca2+ channel antagonist on organ damage, stroke and life span, were examined in stroke prone spontaneously hypertensive rats (SHRSPs). Blood pressure of the SHRSPs increased over the first 16 weeks and reached a stable level of about 250 mmHg in controls and about 200 mmHg in the amlodipine treated group. At 15 weeks after starting amlodipine treatment, all control SHRSPs exhibited varying degrees of myocardial fibrosis, proliferative and/or necrotic vasculitis and glomerular lesions, whereas only a few animals in the amlodipine group showed slight lesions. The average life span of animals was estimated to be 43.3 weeks and 71.1 weeks for control and amlodipine groups, respectively, which suggested a 1.6-fold prolongation of their life span by amlodipine treatment. These results indicate that the long term treatment of amlodipine suppresses the incidence of organ damage and stroke in SHRSPs and prolongs their life span.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8482318&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The action of amlodipine on human subcutaneous resistance arteries studied in vitro.

Garcha RS, Sever PS, Hughes AD.

Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, England.

The effect of amlodipine, a dihydropyridine calcium antagonist which is largely ionized at physiological pH, was studied in human resistance arteries. Resistance arteries were isolated from subcutaneous fat and isometric force measured in a myograph. Amlodipine inhibited depolarization-induced contractions in a time- and concentration-dependent manner. The potency of amlodipine was markedly increased by depolarization of the resistance arteries by a physiological saline containing high potassium (40 mM) during exposure to amlodipine. The onset and offset of amlodipine-induced inhibition in these arteries was slow, but concentration dependent. Depolarization markedly increased the rate of onset of inhibition. The increase in potency of amlodipine under depolarized conditions could largely be accounted for by the increased rate of association of the drug. Possible use-dependence of amlodipine was also examined in comparison with verapamil. The efficacy of both verapamil and amlodipine was increased in vessels which were repeatedly depolarized compared with vessels which were only activated once. This effect was more marked for verapamil than for amlodipine. The action of amlodipine in human resistance arteries is slow, shows marked voltage-dependence and, to a lesser degree, some use-dependence. These properties may be important in understanding the action of amlodipine in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8496831&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on platelet aggregation and blood pressure in patients with essential hypertension.

Hernandez R, Carvajal AR, Armas-de Hernandez MJ, Guerrero-Pajuelo J, Armas-Padilla MC, Barragan O, Machado-de Alvarado I.

Clinical Pharmacology Unit, School of Medicine, Universidad Centro Occidental Lisandro Alvarado, Barquisimeto, Venezuela.

Ten patients (mean age, 46 years) with mild to moderate hypertension received 5 mg of amlodipine daily for 12 weeks. The amlodipine dose was increased to 10 mg daily in 4 patients whose blood pressure remained > or = 90 mmHg during the first 8 weeks. After 8 and 12 weeks of treatment, mean blood pressures in the supine, sitting, and standing positions and after exercise were reduced significantly. Heart rate did not change significantly from before to after treatment. Six hours after amlodipine administration, however, slight but significant increases in heart rate were noted at rest and after exercise. Platelet aggregation induced by adenosine diphosphate or collagen was significantly reduced 6 hours after amlodipine. One patient reported headache after the 10-mg dose of amlodipine. No other side effects were noted. It is concluded that 10 mg of amlodipine once daily is safe and effective in the treatment of mild to moderate hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8519039&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antiproliferative effect of Ca2+ channel blockers on human epidermoid carcinoma A431 cells.

Yoshida J, Ishibashi T, Nishio M.

Department of Pharmacology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.

The effects of Ca(2+) channel blockers on the proliferation of human epidermoid carcinoma A431 cells were investigated by microtiter tetrazolium (MTT) proliferation assay and bromodeoxyuridine (BrdU) incorporation assay. Dihydropyridine derivatives, such as amlodipine, nicardipine, and nimodipine inhibited A431 cell growth and the incorporation of BrdU into cells with IC(50) values of 20-30 microM, while verapamil, diltiazem and dihydropyridine nifedipine inhibited neither the cell growth nor BrdU incorporation at the same concentration. Though extracellular Ca(2+) is indispensable to the cell growth, an L-type Ca(2+) channel agonist, 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl]pyridine-3-carboxylic acid methyl ester (200 nM), did not affect the antiproliferative action of amlodipine. Thapsigargin, an inhibitor of Ca(2+)-ATPase of the endoplasmic reticulum, inhibited itself the growth of A431 cells and also showed a synergistic effect with the antiproliferative action of amlodipine. In the fluorimetric measurement of intracellular free Ca(2+) concentration in fura-2 or fluo-3 loaded A431 cells, amlodipine blunted the thapsigargin- or cyclopiazonic acid-induced Ca(2+) release from endoplasmic reticulum and the ensuing Ca(2+) influx through Ca(2+)-permeable channels. The effect on the thapsigargin-induced Ca(2+) responses could be reproduced by nicardipine and nimodipine but not by nifedipine or verapamil, lacking antiproliferative potency. These findings suggest that the intracellular Ca(2+) control system responsible for thapsigargin- and cyclopiazonic acid-sensitive endoplasmic reticulum, but not L-type Ca(2+) channels, may be modulated by amlodipine, which results in the inhibition of A431 cell growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12860469&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Influence of amlodipine on serum level of some cytokines in patients with congestive heart failure]

[Article in Polish]

Salomon P, Halawa B, Karolko B.

Katedra i Klinika Kardiologii AM we Wroclawiu.

Recent studies showed higher plasma levels of several cytokines, such as interleukines or tumour necrosis factor in patients with congestive heart failure. Cytokines play a very important role in pathogenesis of congestive heart failure, because they impair contractility of heart muscle and cause damage of endothelium and myocytes due to their proinflammatory effects. One of the treatment modalities of heart failure might be administration of drugs inhibiting production of cytokines. The study was undertaken to evaluate whether beneficial effects of amlodipine in congestive heart failure are due to inhibition of synthesis of cytokines. The plasma levels of interleukine 6 (IL-6), tumour necrosis factor (TNF-alpha), neuropeptide Y (NPY) and endothelin-1 (ET-1) were determined in patients with congestive heart failure (NYHA II and III) before and after 30 days of treatment with amlodipine. 40 patients with congestive heart failure (CHF) treated in the Department of Cardiology of Medical University in Wroclaw participated in this study. In all patients CHF developed in the course of ischaemic heart disease and coexisting hypertension. Patients were divided into 2 groups dependingly on the NYHA classification. The first group consisted of 24 patients in II NYHA class, the other one--of 16 patients in III NYHA class. At 8 am, on the second day after admission and before treatment with amlodipine blood samples were taken from examined patients to determine plasma levels of IL-6, TNF-alpha, NPY and ET-1. Then patients were administered amlodipine at the dose of 5-10 mg per day. The next blood samples were taken on 5th and 30th day of treatment. Plasma levels of TNF-alpha, IL-6, NPY and ET-1 were estimated with radioimmunoassay using Medgerix kits. Our findings showed that plasma levels of TNF-alpha, IL-6, NPY and ET-1 in patients with CHF are increased. 30-days treatment with amlodipine caused significant decrease of TNF-alpha and IL-6 levels, but did not influence the plasma levels of NPY and ET-1. Amlodipine causes improvement of circulatory efficiency assessed according to NYHA classification. Treatment with amlodipine may be an additional way of therapy in CHF.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12879778&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
In vivo receptor binding of benidipine and amlodipine in mesenteric arteries and other tissues of spontaneously hypertensive rats.

Yamada S, Nakajima M, Kusaka T, Uchida S, Kimura R.

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan. yamada ys7.u-shizuoka-ken.ac.jp

The present study was undertaken to characterize the in vivo 1,4-dihydropyridine (DHP) receptor binding of long-acting 1,4-DHP calcium channel antagonists in the mesenteric artery and other tissues of SHR. In vivo specific binding of (+)-[3H]PN 200-110 in the SHR mesenteric artery was significantly (36.6-49.7 %) reduced 1-8 h after oral administration of benidipine (1.84 micromol/kg). A greater reduction in (+)-[3H]PN 200-110 binding in the mesenteric artery was observed at a higher dose (5.53 micromol/kg) of this drug. This dose of benidipine also reduced significantly the in vivo specific (+)-[3H]PN 200-110 binding in the aorta but not in the myocardium and cerebral cortex. Following oral administration of amlodipine (17.6 micromol/kg), a significant (51.7-94.2 %) reduction in (+)-[3H]PN 200-110 binding was seen at 1-18 h in the mesenteric artery and at 1-12 h in the aorta. Only a slight reduction in myocardial and cerebral cortical (+)-[3H]PN 200-110 binding was seen following amlodipine administration. In contrast, oral administration of nifedipine (28.9 micromol/kg) reduced markedly in vivo (+)-[3H]PN 200-110 binding in all the tissues of SHR at 1-6 h, and the degree and time-course of the reduction did not differ significantly among the tissues. The area under the curve (AUC) for the receptor occupancy vs time was calculated from the reduction rate (%) of in vivo specific (+)-[3H]PN 200-110 binding. The ratios of the AUCmesenteric artery to AUCaorta or AUCmesenteric artery to AUCmyocardium after oral administration of benidipine and amlodipine were greater than the corresponding value for nifedipine. The degree and time-course of arterial receptor occupancy by benidipine and amlodipine agreed well with those of their hypotensive effects in the conscious SHR. In conclusion, the present study demonstrates that benidipine and amlodipine may occupy, in a more selective and sustained manner, 1,4-DHP receptors in arterial tissues than in other tissues of SHR, and thus, such receptor binding specificity may be responsible for the long-lasting hypotensive effects of these drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12148692&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Sympathoinhibitory and depressor effects of amlodipine in spontaneously hypertensive rats.

Huang BS, Leenen FH.

Hypertension Unit, University of Ottawa Heart Institute, H360, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada.

The authors examined whether central actions contribute to the hypotensive effects of peripherally administered amlodipine, a lipophilic dihydropyridine with slow onset and long duration of action. After 5 to 6 weeks of high (8%, H-Na) or regular (0.6%, R-Na) salt intake, changes in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded at rest and in response to intravenous (iv) and intracerebroventricular (icv) injection, and prolonged iv infusion of amlodipine, in conscious spontaneously hypertensive rats (SHR). Iv injection of amlodipine at 50 to 100 microg/kg decreased MAP but increased RSNA and HR in a dose-related manner. In contrast, icv injection of amlodipine at 10 to 50 microg/kg caused parallel decreases in MAP, RSNA, and HR. Iv infusion of amlodipine at 50 microg/kg per hour for 3 hours followed by 100 microg/kg per hour for 2 hours also decreased in parallel RSNA, MAP, and HR. Maximal decreases in RSNA, MAP, and HR in response to icv injection and iv infusion were significantly larger in SHR on H-Na versus R-Na. All responses lasted at least 1 hour following iv and icv injection, or after the termination of iv infusion of amlodipine. These data suggest that in SHR during prolonged iv infusion, amlodipine appears to cross the blood-brain barrier, block brain l-type Ca2+ channels, and decrease sympathetic outflow and thereby BP. Central actions may prevail during iv infusion of amlodipine at low rates, and the decrease in BP is associated with sympathoinhibition. High salt intake markedly enhances its sympathoinhibitory action, likely through central mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12883316&dopt=Abstract amlodipine Norvasc