amlodipine Norvasc
Opposite effects of amlodipine and enalapril on infarct collagen and remodelling during healing after reperfused myocardial infarction.

Jugdutt BI, Musat-Marcu S.

Walter Mackenzie Health Sciences Centre, University of Alberta, Edmonton, Canada. bjugdutt cha.ualberta.ca

OBJECTIVES: To compare the effects of the calcium channel blocker amlodipine versus the angiotensin-converting enzyme inhibitor enalapril with or without reperfusion on infarct collagen and remodelling during healing after anterior myocardial infarction (MI). ANIMALS AND METHODS: In vivo left ventricular (LV) remodelling and function (by quantitative echocardiography) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion (2 h after anterior MI) or no reperfusion to oral amlodipine (5 mg bid, n=6), enalapril (5 mg bid, n=6), placebo (bid, n=6) or sham surgery (n=6) for six weeks. Ex vivo infarct size, infarct collagen (hydroxyproline), collagen volume fraction and LV topography were measured at six weeks. RESULTS: Compared with placebo controls without reperfusion over six weeks in vivo, enalapril or amlodipine with or without reperfusion produced LV unloading and preserved volumes, shape and function, but enalapril limited LV hypertrophy more than amlodipine. However, compared with no reperfusion, amlodipine preserved infarct wall thickness and shape while enalapril decreased infarct wall thickness and increased the shape index. Ex vivo at six weeks, scar size as a percentage of risk was similar in the MI groups. Importantly, enalapril decreased infarct collagen already lowered by reperfusion, while amlodipine preserved infarct collagen after reperfusion and increased collagen volume fraction in spared myocardium. CONCLUSIONS: Preservation of infarct collagen limits infarct remodelling during healing after reperfused MI and preserves LV shape. Amlodipine and enalapril exert opposite effects on infarct collagen and remodelling after reperfused MI.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10833541&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine inhibits expression of matrix metalloproteinase-1 and its inhibitor in human vascular endothelial cells.

Ikeda U, Hojo Y, Ueno S, Arakawa H, Shimada K.

Department of Cardiology, Jichi Medical School, Tochigi, Japan. uikeda jichi.ac.jp

Matrix metalloproteinase-1 (MMP-1) may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effect of the calcium channel blockers amlodipine and nifedipine on the expression of MMP-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in endothelial cells (ECs). MMP-1 and TIMP-1 levels in conditioned media of human vascular ECs were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescence-labeled collagen digestion. The addition of interleukin-1beta (IL-1beta) increased MMP-1 levels in the culture media of ECs. Amlodipine, but not nifedipine, significantly decreased MMP-1 levels in IL-1beta-stimulated ECs. TIMP-1 levels also were significantly increased by IL-1beta, and its expression was slightly decreased by amlodipine, not by nifedipine. Amlodipine significantly inhibited collagenolytic activity in the culture media of IL-1beta-stimulated ECs, whereas nifedipine showed no significant effect on the activity. Our findings revealed that amlodipine, but not nifedipine, inhibits IL-1beta-induced MMP-1 expression in human ECs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10836722&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Biphasic survival response to amlodipine after myocardial infarction in rats: Association with cardiac vascular remodeling.

Whittaker P, Zhang HP, Kloner RA.

Heart Institute, Good Samaritan Hospital and Department of Medicine, University of Southern California, Los Angeles, CA, USA. pwhittaker dnamail.com

In clinical studies, calcium channel blockers have been found to cause adverse cardiovascular reactions after myocardial infarction; however, such effects appear limited to short-acting agents. Thus, our aim was to evaluate the response to a long-acting calcium channel blocker, amlodipine, in terms of both survival and, cardiac and vascular remodeling after infarction. One week after permanent coronary occlusion, rats were randomized to no treatment or daily amlodipine (5 mg/kg) continued for up to 9 months. Amlodipine resulted in improved survival at 200 days (65% versus 26%; p < 0.05), but no difference at 9 months. However, rats with large infarcts died earlier than untreated animals, while those with smaller infarcts died later or survived for nine months. Amlodipine produced no difference in collagen content in non-infarcted tissue or myocyte cross-sectional area versus untreated hearts; however, scar length was increased. In addition, amlodipine was associated with vascular remodeling; muscle:lumen ratio increased in non-infarcted myocardium as did perivascular fibrosis. Vessels within the scar had reduced lumen area because of smooth muscle proliferation. We also examined infarcted hearts subjected to one week of intravenous amlodipine (1 mg/kg) initiated before occlusion and examined three weeks later. In this study, amlodipine exacerbated muscle proliferation in infarct vessels and was associated with less scar collagen. The vascular remodeling associated with amlodipine treatment is considered unfavorable and so the adverse survival for rats with large infarcts was no surprise. However, the prolonged survival associated with smaller infarcts raises the possibility that these vascular changes, under certain circumstances, are beneficial.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10867358&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Chronic administration of the Ca(2+) channel blocker amlodipine facilitates learning and memory in mice.

Quartermain D.

Department of Neurology, Laboratory of Behavioral Neurology, New York University School of Medicine, 550 1st. Avenue,, New York, NY 10016, USA. quartd01 popmail.med.nyu.edu

Acute administration of the Ca(2+) channel antagonist amlodipine has been shown to facilitate memory for several types of learning in adult animals and to improve retention in aging mice. This study reports three experiments investigating the effect of chronic amlodipine treatment on retention in mice. In the first experiment, groups of mice were treated with either amlodipine or vehicle once a day for 14 days prior to training on a spatial discrimination task. Immediately after training, animals were given a single dose of amlodipine or the vehicle and tested for retention 24 h later. Both groups showed facilitated retention, thereby demonstrating that chronic amlodipine treatment did not produce desensitization to the facilitating effects of a post training treatment. In the second experiment, chronic treatments were administered once daily for 14 days beginning 24 h after training on one-way active avoidance and retention was tested on day 15. Results showed that chronic amlodipine attenuated spontaneous forgetting, but surprisingly, a similar enhancement could be achieved by a single treatment administered 1 day after training. In the third experiment, amlodipine was given either before or immediately after 10 daily training sessions in the one-way active avoidance task. Results showed that chronic treatment accelerated rate of learning. These findings confirm the memory facilitating properties of amlodipine under conditions of chronic drug administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10876023&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Pharmacodynamic interaction between mibefradil and other calcium channel blockers.

Matthes J, Huber I, Haaf O, Antepohl W, Striessnig J, Herzig S.

Department of Pharmacology, University of Koln, Germany.

Briefly after withdrawal of the (T-type) calcium channel blocker mibefradil from the market, four cases of life-threatening interaction of mibefradil with dihydropyridines were reported. We investigated in vitro whether mibefradil interacts with a dihydropyridine, as described for other non-dihydropyridine compounds. Rat working hearts were used to examine functional interactions between amlodipine and mibefradil. Gallopamil and another T-type-channel blocker, ethosuximide, were included for comparison. Effects of mibefradil, (+)- and (-)-gallopamil on [3H](+)-isradipine binding were studied in membranes from tsA201-cells transfected with alpha(1c)-, alpha(2)delta-, and beta(1a)- or beta(2a)-calcium channel subunits. Mibefradil increased negative inotropic effect of amlodipine, but not of gallopamil. Gallopamil and ethosuximide showed no influence on contractile effects of amlodipine. Furthermore, mibefradil concentration-dependently caused bradycardic rhythm disturbance. The same type of arrhythmia was observed combining low concentrations of mibefradil with amlodipine, or with gallopamil, respectively. Amlodipine alone, or the combination of gallopamil or ethosuximide with amlodipine did not cause any arrhythmia. Binding studies showed a concentration-dependent positive allosteric interaction between [3H](+)-isradipine and mibefradil, but not with [3H](+)-isradipine and gallopamil enantiomers. Molecular and functional evidence points to an interaction between a dihydropyridine and mibefradil. Mibefradil caused rhythm disturbances and potentiation of negative inotropy when combined with amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10882031&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of lisinopril and amlodipine on antioxidant status in experimental hypertension.

Mantle D, Patel VB, Why HJ, Ahmed S, Rahman I, MacNee W, Wassif WS, Richardson PJ, Preedy VR.

Department of Neurochemistry, Regional Neurosciences Centre, Newcastle General Hospital, NE4 6BE, Newcastle upon Tyne, UK.

The objective of this investigation was to compare changes in antioxidant status (together with other metabolites relevant to hypertension) in plasma and cardiac tissue from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), following 8 weeks of treatment with lisinopril (angiotensin converting enzyme inhibitor) or amlodipine (Ca(2+) channel antagonist) respectively. There was no significant difference in the levels of total antioxidant capacity, retinol, urea, albumin or triglyceride in plasma from SHR or WKY rats, with or without lisinopril or amlodipine treatment. However in SHR rats, levels of alpha-tocopherol were substantially reduced in both plasma (-54% WKY, P<0.01) and cardiac tissue (-43% WKY, P<0.05). Treatment with lisinopril ameliorated reduced levels of plasma alpha-tocopherol in SHR rats, but not in cardiac tissue. Amlodipine treatment had no effect on alpha-tocopherol levels in plasma or cardiac tissue in SHR rats. In SHR rats total cholesterol levels were significantly lower thanWKY controls (-36%, P<0.001). This effect was reversed in lisinopril treated SHR rats (+27%, P<0.01). Plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were reduced in untreated SHR rats (P<0.025) when compared to WKY controls; neither lisinopril nor amlodipine treatment significantly altered these parameters. These findings suggest possible alternative mechanisms of action for lisinopril, and reinforce its use in hypertensive patients or patients with left ventricular hypertrophy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10900288&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The inhibitory mechanisms of amlodipine in human vascular smooth muscle cell proliferation.

Zhang YZ, Gao PJ, Wang XY, Stepien O, Marche P, Zhang ZL, Zhu DL.

Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Second Medical University, PR China.

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is closely related to vascular diseases. There is growing evidence that calcium antagonists inhibit VSMC growth/proliferation, yet their molecular mechanisms remain to be determined. Recent reports suggest that p42/p44 mitogen-activated protein kinases (MAPKs) play an important role in cell growth and proliferation induced by growth factors. This study was designed to determine whether these MAPKs are involved in VSMC proliferation induced by basic fibroblast growth factor (bFGF) and to examine the inhibitory effect of amlodipine. Human VSMCs were obtained from inner mammary artery. p42/p44 MAPKs activity was measured by immunoblotting assay using anti-p42/p44 phospho-MAPK antibody. 1) bFGF (20 ng/ml) significantly activated p42/p44 MAPKs with a peak time of 5-15 min, which was maintained for 3 h. PD98059 (100 nM-10 microM), a specific inhibitor of MAPK kinase, inhibited bFGF-induced p42/p44 MAPKs activation in a dose-dependent manner. 2) Amlodipine (1-100 nM) dose-dependently inhibited p42/p44 MAPKs activation by bFGF. 3) Amlodipine (10 nM) could inhibit both short-term and long-term p42/p44 MAPKs activation by bFGF. Our results indicate that bFGF could activate p42/p44 MAPKs. Amlodipine, which could inhibit bFGF-induced human VSMC proliferation, inhibited both short-term and sustained p42/p44 MAPKs activation by bFGF, suggesting that bFGF-induced VSMC proliferation may be related to p42/p44 MAPKs activation, and that the antiproliferative effect of amlodipine may be related to its inhibition of p42/p44 MAPKs activation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10912781&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Influence of the timing of initiating antihypertensive therapy in hypertensive rats with renal failure.

Kanno Y, Okada H, Takenaka T, Saruta T, Suzuki H.

Department of Nephrology, Saitama Medical School, Iruma, Japan.

The important contribution of hypertension to the progression of renal failure is well realized. However, it have been less discussed which drugs are suitable for the different stages of progressive renal failure. The present study examined the effects of timing of antihypertensive therapy using calcium channel blocker and angiotensin converting enzyme inhibitor in 5/6 nephrectomized spontaneously hypertensive rats (SHRs). Forty male 6 week old SHRs were divided into 5 groups (n=8 in each group), and they were placed on a high salt diet after 5/6 nephrectomy. Group 1, high salt diet without any drug. Group 2 received 0.2 mg/kg/day of amlodipine and group 3 received 0.2 mg/kg/day of enalapril mixed in the high salt diet from week 6 respectively. Similarly group 4 received the same doses of amlodipine, and group 5 received the same doses of enalapril from week 10. Each drug protected from increasing blood pressure in 4 groups, and no significant difference was observed between the effects of amlodipine and enalapril. Proteinuria was reduced with both drugs. In histopathological evaluation, glomerulosclerosis was controlled only in group 2, and arterio/olosclerosis was significantly suppressed in all treated groups except group 5. From these results, both amlodipine and enalapril are renal protective in early stage of renal failure with hypertension. However, in advanced stage of renal failure, amlodipine is superior in its renal protective effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10937842&dopt=Abstract amlodipine Norvasc