amlodipine Norvasc
Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats.

Sandmann S, Claas R, Cleutjens JP, Daemen MJ, Unger T.

Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany. s.sandmann pharmakologie.uni-kiel.de

Calcium channel antagonists (CCAs) have been proposed to prevent cardiac events after myocardial infarction (MI). However, unwanted effects, such as negative inotropy, limit their use in many cases. The aim of this study was to compare the effects of long-term treatment with the CCAs, mibefradil, verapamil, and amlodipine, administered before and after chronic MI on myocardial remodeling and cardiac function. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Infarcted animals were treated with placebo, mibefradil (10 mg/kg/d po), verapamil (8 mg/kg bid po), or amlodipine (4 mg/kg/d po). Treatment was started 7 days before or 3 h after MI induction. Six weeks after MI, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), and cardiac contractility (dP/dt(max)) were measured. Morphometric parameters such as infarct size (IS), left ventricular dilation (LVD), septal thickness (ST), and cardiac fibrosis were determined in picrosirius red-stained hearts. Six weeks after MI, MAP and dP/dt(max) were decreased, whereas LVEDP and HR were increased in placebo-treated controls. The hearts featured an IS of 45%, left ventricular dilation, cardiac fibrosis, and septal thinning. MAP of all CCA-treated animals was increased, whereas LVEDP was decreased and dP/dt(max) increased 7-day pre- and 3-h post-MI started in mibefradil- and amlodipine-treated animals, but not in verapamil-treated animals. In contrast to amlodipine treatment, before and after MI started mibefradil and verapamil treatment decreased HR. Pretreatment with all CCA reduced IS and increased ST, whereas only mibefradil and amlodipine pretreatment prevented LVD and cardiac fibrosis. After MI started treatment with mibefradil and amlodipine reduced IS and cardiac fibrosis, and increased ST. Long-term treatment with the CCAs mibefradil, verapamil, and amlodipine reduced myocardial remodeling and improved cardiac function in MI-induced heart failure in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11152376&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of amlodipine on cardiopulmonary performance in volunteers.

Lay L, Bjorksten AR, Stainsby GV, Blake DW.

Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.

1. In order to exclude a significant effect of the calcium channel antagonist amlodipine on cardiopulmonary performance in normal subjects, we performed a double-blind cross-over study of amlodipine (10 mg daily for 2 weeks) on oxygen uptake and catecholamine responses during exercise in eight volunteers. 2. Despite a therapeutic plasma concentration of amlodipine (22.8+/-9 ng/mL), there was no change in resting heart rate or blood pressure. Amlodipine did not cause significant change in oxygen uptake at the anaerobic threshold or at maximum exercise and there was also no change in heart rate or catecholamine responses. 3. Although there was an awareness of peripheral vasodilation and reports of lethargy during the active treatment period, the volunteers had no objective evidence of a decrease in cardiopulmonary performance. We suggest that use of amlodipine as a vasodilator in the perioperative period would not add to the myocardial depressant effects of general anaesthesia in patients with normal cardiac function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11153533&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Enzyme linked immunosorbent assay for determination of amlodipine in plasma.

Matalka K, El-Thaher T, Saleem M, Arafat T, Jehanli A, Badwan A.

Faculty of Pharmacy and Medical Technology, The University of Petra, Amman, Jordan. jpm go.com.jo

Amlodipine is a calcium channel antagonist of the dihydropyridine group. It is effective for treating hypertension, chronic stable angina, and vasospastic angina. However, it is difficult clinically to pinpoint the maximum dosage for antihypertensive activity of the drug without having parallel data on the plasma drug concentrations. The methods for assaying amlodipine are either gas chromatography with electron capture detector or liquid chromatography coupled with tandem mass spectrometry (or with an electrochemical detector), which needs tedious derivatization, and is expensive and time consuming. Therefore, in this study we developed an enzyme immunoassay for determining amlodipine in plasma. Anti-amlodipine antibodies were produced following immunization of bovine serum albumin-amlodipine conjugate. These specific antibodies were used in a competitive biotin-avidin-based enzyme-linked immunosorbent assay to measure amlodipine in plasma. Biotin was linked to the antibodies in order to enhance the sensitivity of the assay. The assay was specific for the free form of amlodipine with a detection limit of 0.1 ng/ml and the intra- and interassay coefficient of variation ranged from 1.6-10.2%. This immunoassay provides a sensitive, reliable, rapid, and accurate method for determination of amlodipine in plasma, which can be used in therapeutic drug monitoring pharmacokinetic studies and pharmaceutical analysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11170235&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Normalisation of blood pressure in hypertensive TGR(mREN2)27 rats by amlodipine vs. enalapril: effects on cardiac hypertrophy and signal transduction pathways.

Witte K, Huser L, Knotter B, Heckmann M, Schiffer S, Lemmer B.

Institute of Pharmacology and Toxicology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany. klaus.witte urz.uni-heidelberg.de

It is still a controversial issue whether different classes of antihypertensive drugs are equally effective in the regression of cardiac hypertrophy and associated complications. The present study compared the effects of prolonged treatment with the Ca2+-channel blocker amlodipine and the ACE inhibitor enalapril, respectively, in TGR(mREN2)27 rats (TGR), an animal model of renin-dependent hypertension. TGR were divided into three groups and received either amlodipine, enalapril or drinking water without addition, Sprague-Dawley rats (SPRD) served as normotensive control group. Cardiovascular parameters were monitored by radiotelemetry, and drug doses were titrated until 24-h blood pressure was reduced to approximately 140/90 mmHg in both active treatment groups. After 8 weeks of treatment left ventricular (LV) hypertrophy was completely reversed in both treatment groups despite a tenfold increase in plasma angiotensin II in amlodipine-treated TGR. In untreated TGR LV catecholamines were depleted, and beta1-adrenergic stimulation of adenylyl cyclase was blunted. Treatment of TGR with enalapril prevented both the depletion of tissue catecholamines and the desensitisation of LV beta1-adrenoceptors. Amlodipine had no effect on cardiac adrenergic signal transduction. Basal activity of LV soluble guanylyl cyclase was not different between TGR and SPRD, but its sensitivity to stimulation by nitric oxide was slightly reduced in TGR. Treatment had no effect on basal and stimulated guanylyl cyclase activity. The present study in an animal model of renin-dependent hypertension suggests that blood pressure reduction per se is sufficient for a regression of cardiac hypertrophy. However, beta-adrenergic desensitisation was prevented only in the enalapril-treated group, supporting a blood pressure-independent contribution of the renin-angiotensin system to the regulation of beta-adrenergic signal transduction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11191827&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of amlodipine on echocardiographic variables in cats with systemic hypertension.

Snyder PS, Sadek D, Jones GL.

Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville 32610, USA. snyderp mail.vetmed.ufl.edu

Left ventricular hypertrophy signals a poor prognosis in hypertensive humans. Cardiac disease is common in cats with systemic hypertension. The aims of this study were to characterize the echocardiographic findings of cats with systemic hypertension and to determine if reducing the degree of hypertension is associated with resolution of cardiac hypertrophy. Echocardiographic examinations were performed on 19 cats with naturally occurring systemic hypertension. Fourteen of these cats were subsequently studied after a minimum of 3 months of treatment with the antihypertensive agent amlodipine. Hypertensive cats had a significantly thicker interventricular septum in both systole and diastole, thicker left ventricular free wall in both systole and diastole, and larger left atrium compared to the published normal values and 74% (14/19) of the cats met criteria for left ventricular hypertrophy (diastolic septal or free-wall thickness > 0.60 cm). Systolic blood pressure was lower after treatment (217 +/- 25 mm Hg, range: 180-275 mm Hg; and 142 +/- 27 mm Hg, range: 90-200 mm Hg). No difference was found in any of the echocardiographic measurements between the untreated and treated cats, although more cats had ventricular hypertrophy before treatment (11/14) than after initiating amlodipine (6/14; P = .006). Ventricular hypertrophy is common in hypertensive cats and may resolve after the initiation of amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11215913&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Pulmonary vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril.

Jeffery TK, Wanstall JC.

Pulmonary Pharmacology Group, Department of Physiology and Pharmacology, The University of Queensland, St Lucia, Qld 4072, Brisbane, Australia.

This study investigated whether pulmonary vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (10 mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 microm o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Thus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11282121&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on serum levels of adrenal androgens and insulin in hypertensive men with obesity.

Ueshiba H, Tsuboi K, Miyachi Y.

First Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan. ueshiba med.toho-u.ac.jp

We investigated the effects of the calcium channel blocker amlodipine besilate on serum levels of adrenal androgens and insulin in 20 men with essential hypertension and obesity (age: 51.9+/-4.7 years, body mass index: 27.7+/-1.5 kg/m2). All were treated with amlodipine besilate (Norvasc) for 3 months. Blood pressure, fasting plasma glucose (FPG), HbA1c and serum levels of insulin, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and lipids were measured before and after a 3-month period. In 10 patients, 75 g oral glucose tolerance test (75 g-OGTT) was also performed. Amlodipine besilate treatment 1) lowered the fasting serum insulin level and total serum insulin level during 75 g-OGTT and 2) increased serum DHEA and DHEA-S levels. No changes in fasting plasma glucose, HbA1c and serum lipids were observed during treatment. We conclude that amlodipine besilate improves insulin resistance and consequently increases serum DHEA and DHEA-S levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11355751&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model.

Griffin KA, Picken M, Bakris GL, Bidani AK.

Departments of Medicine, Loyola University Medical Center and Hines Veterans Administration Hospital, Maywood, IL 60153, USA.

We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is approximately 10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141+/-3 mm Hg) and amlodipine (143+/-5 mm Hg) compared with untreated rats (188+/-5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (r=0.74 to 0.85, P<0.02). However, the slope of the relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7+/-0.2; P<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11358939&dopt=Abstract amlodipine Norvasc