amlodipine Norvasc
Effect of amlodipine pretreatment on ischaemia-reperfusion-induced increase in cardiac endothelin-1 binding site density.

Nayler WG, Ou RC, Gu XH, Casley DJ.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.

Endothelin-1 (ET-1) may be implicated in the pathophysiology of myocardial ischaemia. To determine whether the long-acting calcium antagonist amlodipine attenuates the ischaemia- and reperfusion-induced increase in cardiac ET-1 binding sites, hearts from rats pretreated with amlodipine (0.25 or 0.5 mg/kg) 2 or 5 h before they were killed were made ischaemic for 20 or 40 min, reperfused, and subfractionated. Twenty- and 40-min ischaemia caused a time-dependent increase in ET-1 binding site density (Bmax) identified with [125I]ET-1. Amlodipine pretreatment attenuated this increase in a time- and dose-dependent manner. 0.25 and 0.5 mg/kg amlodipine also suppressed the reperfusion-induced increase in [125I]ET-1 binding site density, even when the 0.5-mg/kg pretreatment series reperfusion was administered after 40-min ischaemia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1279286&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Absence of hemodynamic deterioration in the presence of amlodipine following experimental myocardial infarction.

Kloner RA, Hale SL, Alker KJ.

Heart Institute Research Department, Hospital of the Good Samaritan, Los Angeles, California 90017.

In general, calcium channel blockers have not been used in patients during acute myocardial infarction as they may exacerbate heart failure, possibly by neuro-humoral stimulation. Amlodipine, a new dihydropyridine calcium channel blocker without neurohumoral stimulation, was tested in an experimental model of acute myocardial infarction with assessment of hemodynamics, left ventricular (LV) function, and infarct size. Anesthetized dogs were subjected to 3 h of coronary artery occlusion followed by 3 h of reperfusion. At 2 h of occlusion, they were randomized to receive either amlodipine (250 micrograms/kg, n = 11) or saline (n = 11). Before treatment, all variables were similar in both groups. The diastolic pressure was unchanged following saline, but was reduced following amlodipine by 1 h after therapy (from 94 +/- 5 to 71 +/- 3 mm Hg, p < 0.0001 vs. saline) and for the duration of the protocol. Indices of left ventricular (LV) function did not deteriorate with amlodipine treatment compared with saline. After 3 h of reperfusion, the LV dP/dt was 1,720 +/- 114 mm Hg/s in the saline group and 1,958 +/- 167 mm Hg/s with amlodipine (p = ns). The area ejection fraction, assessed by echocardiography, was similar in both groups (43 +/- 5%, saline; 45 +/- 3%, amlodipine; p = ns), as was the LV end-diastolic pressure (8 +/- 1 mm Hg, saline; 7 +/- 1 mm Hg, amlodipine; p = ns). Subendocardial regional myocardial blood flow, measured by radioactive microspheres, was 0.75 +/- 0.08 ml/min/g with saline and 1.34 +/- 0.33 ml/min/g with amlodipine in the previously ischemic reperfused subendocardium (p = 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
The antiatherogenic effects of amlodipine: promise of preclinical data.

Nayler WG.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.

Atherosclerosis is a complex and multifactorial disease, the endpoint of which is the formation of a calcified plaque. Intermediate events include intimal injury, smooth muscle cell proliferation and migration, macrophage infiltration, lipid accumulation and excess formation of ground substance. To determine whether the newly developed, long-acting calcium antagonist, amlodipine, slows the development of atherosclerotic lesions under experimental conditions, young New Zealand white rabbits were fed on a diet of 2% cholesterol plus 1% peanut oil for up to 12 weeks. Half the rabbits received 1 or 5 mg amlodipine/kg body weight/day. Amlodipine caused a significant and dose-dependent reduction in lesion formation in the thoracic aorta. At the same time thoracic aorta Ca2+ and cholesterol content were maintained at near normal levels, despite the raised plasma cholesterol levels. The protective effect of amlodipine persisted throughout a treatment period of 12 weeks, indicating the absence of tachyphylaxis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1284082&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on myocardial infarction, infarct expansion, and ventricular geometry in the rat.

Hagar JM, Newman LG, Kloner RA.

Heart Institute, Hospital of the Good Samaritan, Los Angeles, CA 90017.

Infarct expansion remains an important sequela of myocardial infarction. Both angiotensin converting enzyme inhibitors and intravenous nitrates reduce early infarct expansion in humans. This is believed to be caused by the reduction in left ventricular systolic wall stress that results from the arteriolar vasodilatation they produce. Patients are frequently already receiving calcium channel blockers at the time of infarction or these drugs are sometimes administered in the perimyocardial infarction period. The calcium blockers of the dihydropyridine class might be expected to modify infarct expansion. However, their effect on this process has not been studied. We therefore evaluated the effect of early treatment with the calcium blocker amlodipine, a potent arteriolar vasodilator with minimal negative inotropic properties, on chronic myocardial infarction in the rat. Permanent left coronary occlusion was created after pretreatment with amlodipine, 0.25 mg/kg (low dose) or 1.0 mg/kg (high dose), or placebo, intravenously twice a day, and continued for 7 days after infarction. Hearts (n = 50) were perfusion fixed 21 days after infarction and analyzed for infarct extent, scar thickness, left ventricular shape and size, and expansion index. Both doses decreased mean blood pressure (119 +/- 3 to 99 +/- 5 mm Hg low dose, p = 0.004; 110 +/- 5 to 84 +/- 4 mm Hg high dose, p = 0.0003), with reflex tachycardia only after the high dose (heart rate 395 +/- 9 to 434 +/- 11, p = 0.001). Infarct extent was equal in the three groups (39 +/- 2%, 41 +/- 2%, and 41 +/- 3% of left ventricular circumference for control, low, and high doses, respectively). The three groups did not differ significantly with regard to left ventricular cavity cross-sectional area (80 +/- 4, 77 +/- 3, and 87 +/- 3 mm2, control, low, and high doses, respectively; p = 0.07 high dose vs control), mean scar thickness (0.74 +/- 0.06, 0.73 +/- 0.05, and 0.65 +/- 0.06 mm, control, low, and high doses, respectively; p = NS), and expansion index (1.52 +/- 0.10, 1.58 +/- 0.12, and 1.95 +/- 0.19, control, low, and high doses, respectively; p = 0.08 high dose vs control). In the subgroup with larger infarcts (infarct extent greater than 0.39 of left ventricle), the expansion index was higher in the high-dose group (2.37 +/- 0.23 vs 1.64 +/- 0.17 control; p = 0.04). In this model, treatment with amlodipine does not limit infarct extent or reduce early infarct expansion and left ventricular dilatation, even when initiated before infarction.(ABSTRACT TRUNCATED AT 400 WORDS)

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amlodipine Norvasc
Effects of amlodipine on plasma lipid and lipoprotein levels in hypertensive patients.

Ahaneku JE, Taylor GO, Agbedana EO, Walker O, Sowunmi A, Salako LA.

Department of Pathology, College of Health Sciences, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria.

Lipids and lipoprotein levels were determined in the plasma of 20 adult hypertensive patients, after 12 weeks treatment with amlodipine. No significant variation was observed in the mean values of the lipids and lipoprotein fractions before and after amlodipine treatment for the patients on either 5 mg or 10 mg of amlodipine. A further long-term study has been suggested in order to confirm the inertness of amlodipine on lipids and lipoprotein metabolism.

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amlodipine Norvasc
Cholesterol alters the binding of Ca2+ channel blockers to the membrane lipid bilayer.

Mason RP, Moisey DM, Shajenko L.

Department of Radiology, University of Connecticut Health Center, Farmington 06030.

X-ray diffraction and equilibrium binding techniques were used to study the effect of cholesterol on membrane binding of the charged 1,4-dihydropyridine (DHP) Ca2+ channel antagonist amlodipine and uncharged isradipine, nimodipine, and nitrendipine. Increases in membrane cholesterol content resulted in a marked decrease in DHP binding to cardiac phospholipid membranes, as expressed by the equilibrium partition coefficient (Kp[mem]). Between a 0:1 and 0.3:1 cholesterol to phospholipid mole ratio, the Kp(mem) values for isradipine, nimodipine, and nitrendipine decreased by greater than 50%, whereas that for amlodipine decreased by only 10%. Electron density profiles calculated from the X-ray diffraction data showed that the time-averaged locations for the DHPs and cholesterol in the membrane overlap, leading to the conclusion that the addition of cholesterol alters the lipid bilayer hydrocarbon core structure in a manner that makes drug partitioning into the membrane less energetically favorable. These data support the idea that drug interactions with the anisotropic membrane environment are complex and may be greatly influenced by cholesterol composition. This effect of cholesterol was also observed for phenylalkylamine (verapamil) and benzothiazepine (diltiazem) Ca2+ channel blockers. The DHP amlodipine had the highest membrane partition coefficient (Kp[mem] greater than 10(4) and the slowest rate of dissociation and was affected least by membrane cholesterol content. The combination of electrostatic and hydrophobic bonding between amlodipine and membrane phospholipid may explain the high affinity of this drug for the membrane bilayer with normal and elevated cholesterol. The results of this study show that cholesterol content differentially affects the membrane-binding properties of the charged DHP amlodipine, compared with other Ca2+ channel blockers. These data help explain the biological distribution of these drugs and the distinct pharmacokinetics of amlodipine versus other Ca2+ channel blockers.

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amlodipine Norvasc
Inhibition of cancer cell growth by calcium channel antagonists in the athymic mouse.

Taylor JM, Simpson RU.

Department of Pharmacology, University of Michigan, Ann Arbor 48109-0626.

The calcium channel antagonists (CCAs) amlodipine, diltiazem, and verapamil inhibited HT-39 human breast cancer cell proliferation in a concentration-dependent manner. The apparent 50% inhibitory dose values were 1.5 microM for the dihydropyridine amlodipine, 5 microM for the benzothiazapine diltiazem, and 10 microM for the phenylalkylamine verapamil. Amlodipine treatment caused a rapid concentration-dependent decrease of intracellular calcium concentration in the HT-39 cell line. Addition of 1 microM amlodipine had no effect on intracellular calcium levels, 3 microM amlodipine lowered intracellular calcium levels in the HT-39 cells by 13.7%, and 10 microM amlodipine lowered intracellular calcium levels by 33.2%. Also, lowering medium calcium levels from 2.0 mM to 0.5 microM resulted in a rapid 41.3% decrease in intracellular calcium and a concomitant 60% inhibition of HT-39 cell DNA synthesis. When HT-39 cells were transplanted into athymic mice, marked hypercalcemia developed. Serum calcium levels from control mice were 8.3 +/- 0.6 mg/dl (mean +/- SE; n = 4); those from tumor-bearing mice were 11.3 +/- 0.08 mg/dl (mean +/- SE; n = 17). Blood calcium levels correlated directly with tumor size (r = 0.91, P less than 0.01). We examined the capacity of three CCAs to specifically inhibit HT-39 tumor growth in vivo. One week after inoculation of HT-39 cells, mice were acclimated to vehicle or 0.1 mg/day amlodipine, 1.0 mg/day diltiazem, or 1.0 mg/day verpamil, in their drinking water, for 7 days. Oral administration of the dihydropyridine amlodipine (0.35 mg/day) for 10 days inhibited HT-39 breast tumor growth by 83.5 +/- 20.1% (mean +/- SE). Oral administration of diltiazem (3.5 mg/day) inhibited HT-39 breast tumor growth rate by 46.5 +/- 6.6% over a 2-week measurement period, and verapamil (3.5 mg/day) inhibited tumor growth rate by 68.2 +/- 9.7% (mean +/- SE). The CCAs had no effect on mouse body weight or gross organ morphology at the concentrations used. Lack of depolarization-induced calcium fluxes in the HT-39 cell line suggests that these cells do not express voltage-operated calcium channels. Thus, our study correlates an effect of amlodipine to lower intracellular calcium levels, by a mechanism not known at present, with its effect to inhibit HT-39 cell proliferation. These findings are important since they demonstrate that amlodipine and other CCAs with known pharmacodynamics and side effects act to blunt breast tumor progression in vivo.

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amlodipine Norvasc
Beneficial actions of amlodipine in the multiple-stunned canine myocardium.

Gross GJ, Pieper GM.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.

The effects of the long-acting dihydropyridine calcium-entry blocker, amlodipine, on subendocardial segment shortening (%SS), regional myocardial blood flow (radioactive microspheres), and tissue high-energy phosphate levels were compared with those of a saline-treated group of barbital-anesthetized dogs subjected to nine 5-minute coronary artery occlusions interspersed with 15 minutes of reperfusion and finally by 1 hour of reperfusion (multiple stunned myocardium). Saline or amlodipine (200 micrograms/kg, IV) were administered 15 minutes prior to the first coronary occlusion. There were no major differences between groups in ischemic bed size or hemodynamics throughout the experiment. Subendocardial collateral blood flow was significantly increased in the amlodipine-treated group during coronary occlusion 1; however, tissue blood flow in the ischemic region was not significantly different between groups during occlusion 9. Following each occlusion, %SS in the ischemic region was equally reduced in both groups and passive systolic lengthening resulted. In spite of similar decreases in %SS during occlusion, the amlodipine-treated dogs showed a marked improvement in myocardial segment function (%SS) of the ischemic-reperfused region at 15 minutes following each occlusion (1-9) and at 15, 30, and 60 minutes of reperfusion following occlusion 9, as compared to saline-treated animals. In addition, amlodipine attenuated the loss of adenine nucleotides in the ischemic-reperfused area at 1 hour of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the multiple-stunned myocardium and may have potential as a cardioprotective agent for the treatment of myocardial reperfusion injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1533534&dopt=Abstract amlodipine Norvasc