amlodipine Norvasc
Effects of alacepril and amlodipine on the renal injury induced by a high-cholesterol diet in rats.

Atarashi K, Takagi M, Minami M, Ishiyama A.

The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.

BACKGROUND: A high-cholesterol (HC) diet increases blood pressure and induces renal injury in rats. We compared the effects of alacepril, an ACE inhibitor, and amlodipine, a Ca antagonist, on the renal injury induced by an HC diet in rats. DESIGN AND METHODS: Male Sprague-Dawley rats were given either an HC diet only (n = 5), an HC diet and amlodipine (n = 10) or an HC diet and alacepril (n = 10). The control rats (n = 5) were given a normal diet Systolic blood pressure (SBP) was measured by a tail-cuff method. Serum lipids, malondialdehyde (MDA) as a parameter for lipid peroxidation and urinary protein excretion were determined at 0, 4 and 8 weeks. The renal injury was evaluated histologically by the glomeruli sclerosing score. RESULTS: The HC diet increased SBP. Amlodipine lowered SBP more significantly than alacepril. Serum total cholesterol was increased by the HC diet and was not affected by either anti-hypertensive agent. HDL-cholesterol was similarly decreased in the three HC diet groups. Alacepril, but not amlodipine, completely attenuated the MDA elevation induced by the HC diet. Urinary protein excretion was decreased by the two anti-hypertensive agents at a similar rate. The renal histological injury assessed by the sclerosing score was ameliorated more significantly by alacepril than by amlodipine. CONCLUSIONS: Both amlodipine and alacepril decreased blood pressure and urinary protein, and ameliorated the renal injury induced by the HC diet in rats. The renal effect of alacepril seems to be mediated by the decrease in oxidative stress as well as by reduction of blood pressure, since alacepril lowered the sclerosing score more than amlodipine and completely attenuated MDA, although the blood pressure reduction by alacepril was less than that by amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10703899&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine inhibits the production of cytokines induced by ouabain.

Matsumori A, Ono K, Nishio R, Nose Y, Sasayama S.

Department of Cardiovascular Medicine, Kyoto University, Japan. amaat kuhp.kyoto-u.ac.jp

Recent studies have suggested that cytokines are capable of modifying cardiovascular function and that drugs used in the treatment of heart failure have various modulating properties on the production of cytokines. More recently, we have found that ouabain induces the production of cytokines. This study was performed to examine the effects of calcium channel blockers on the production of cytokines induced by a cardiac glycoside. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured in 0.1, 1, 10, and 30 micromol/l amlodipine, diltiazem, and nifedipine in presence of 1 micromol/l ouabain. After 24 h of incubation, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were measured in the culture supernatants by enzyme-linked immunosorbent assay. Ouabain induced the production of IL-1alpha, IL-1beta and IL-6, but not of TNF-alpha. Induction of IL-1beta was most prominent. The production of IL-1alpha, and IL-6 was inhibited by amlodipine in a concentration-dependent manner and was significantly decreased at a concentration of 10 micromol/l. IL-1beta production was also inhibited by 30 micromol/l amlodipine. In contrast, neither diltiazem nor nifedipine inhibited the production of these cytokines. The unique property of amlodipine to inhibit the production of IL-1alpha, IL-1beta and IL-6 may contribute to its beneficial effects in heart failure patients. Copyright 2000 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10704258&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
INFLUENCE OF BASELINE VALUES ON LIPIDS, LIPOPROTEINS AND FIBRINOLYTIC PARAMETERS DURING AMLODIPINE TREATMENT OF HYPERTENSION IN JAPANESE PATIENTS.

Ahaneku JE, Sakata K, Urano T, Takada Y, Takada A.

Second Department of Physiology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu-shi, Shizuoka-ken, 431-3192, Japan,

Twenty-four Japanese hypertensive patients of both sexes, grouped as having 'medium' and 'high' baseline total lipid values, had their serum lipids, lipoproteins and plasma fibrinolytic parameters, renin and noradrenaline levels determined after 3 months of amlodipine treatment. For the patients with 'medium baseline values', total plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complex levels decreased, while the changes in lipids and lipoproteins were not significant after amlodipine treatment. For the patients with 'high baseline values', the mean triglyceride and very low density lipoprotein cholesterol (VLDLC) levels were reduced while the reductions in total and free PAI-1 and the increase in tissue plasminogen (t-PA) levels were not significant after amlodipine treatment. Negative correlations were observed between t-PA and high density lipoprotein cholesterol (HDLC) and HDLC/total cholesterol (TC) ratio in the patients with 'medium baseline values' while t-PA positively correlated with HDLC/TC ratio in patients with 'high baseline values'. The mean levels of renin and noradrenaline remained unchanged before and after amlodipine treatment in the two baseline groups. These findings show that baseline lipid levels of the hypertensive patients could influence lipids and fibrinolytic parameters differently during amlodipine treatment. The baseline lipid levels also influenced the metabolic association between lipids and fibrinolytic function in hypertensive patients during amlodipine treatment. The baseline total lipid values could therefore provide explanations for the complex metabolic interaction between lipids and fibrinolytic function as well as for the antiatherogenic actions of amlodipine treatment in hypertensive patients. 2000 Academic Press p$hr Copyright 2000 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10712829&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats.

Kim S, Zhan Y, Izumi Y, Iwao H.

Department of Pharmacology, Osaka City University Medical School, Abeno-ku, Osaka, Japan. kims med.osaka-cu.ac.jp

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10720593&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts.

Mital S, Loke KE, Slater JP, Addonizio L, Gersony WM, Hintze TH.

Columbia University College of Physicians and Surgeons, New York, New York, USA.

The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10750596&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Calcium antagonists and vascular smooth muscle cell reactivity.

Marche P, Stepien O.

CNRS UMR 8604 Faculte de Medecine Necker, Paris, France. marche necker.fr

OBJECTIVES: To determine the mechanisms whereby calcium channel blockers (CCBs) control the reactivity of vascular smooth muscle cells (VSMCs). BACKGROUND: Although CCBs are known to play an important role in the calcium homeostasis of VSMCs, they are suspected to exert additional effects in this cell type. Thus, the possibility that CCBs could affect VSMC growth/proliferation through a mechanism distinct from the inhibition of calcium channels was investigated. METHODS: VSMCs were isolated from rat aortae and cultured. The influence of nifedipine and amlodipine on basic fibroblast growth factor (bFGF)-stimulated DNA synthesis and proliferation was studied by measuring bFGF-induced BrdU incorporation into VSMCs and cell counts, respectively. The influence of amlodipine (and of isradipine) on the mobilization of intracellular Ca2+ stores was determined by studying the fluorescence of thapsigargin-stimulated VSMCs pre-labeled with the fluoroprobe Fura-2. RESULTS: Both nifedipine and amlodipine inhibited bFGF-induced VSMC growth/proliferation. In the case of nifedipine but not in that of amlodipine, this inhibitory effect could be accounted for by the L-type Ca(2+)-channel antagonist property of the drug. On the other hand, amlodipine but not isradipine, diltiazem, and verapamil, did inhibit thapsigargin-induced Ca2+ mobilization. CONCLUSIONS: These findings suggest that in addition to its L-type Ca(2+)-channel antagonist property, amlodipine also exerts a "thapsigargin-like" activity which, together with its particular antioxidant property, might participate in its antiatherogenic potency.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10769418&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Energy-dependent accumulation of calcium antagonists in catecholamine storage vesicles.

Terland O, Flatmark T.

Department of Biochemistry and Molecular Biology, University of Bergen, Norway.

The calcium antagonists verapamil, nitrendipine, mibefradil, and amlodipine accumulate in chromaffin granule ghosts with apparent equilibrium partition coefficients [(mol/mg membrane lipid)/(mol/mg solvent water)] of 246 +/- 105 (N = 8), 2700 +/- 600 (N = 4), 7400 +/- 2200 (N = 4), and 8100 +/- 1100 (N = 5), respectively. In the presence of 1.2 mM MgATP, the partition coefficients were 854 +/- 206 (N = 10), 2300 +/- 600 (N = 4), 32,700 +/- 8,900 (N = 7), and 20,300 +/- 5,000 (N = 11) for verapamil, nitrendipine, mibefradil, and amlodipine, respectively. Except for nitrendipine, the apparent partition coefficients in the presence of MgATP were significantly different from the control (P < 0.001). For amlodipine and verapamil, the vacuolar H(+)-ATPase inhibitors bafilomycin A1 (30 nM) and N-ethylmaleimide (2 mM) and the protonophore (uncoupler) carbonyl cyanide m-chlorophenylhydrazone (CCCP, 10 microM) completely blocked the increase in partition coefficients in response to MgATP. The extra amlodipine, mibefradil, and verapamil that accumulated in response to MgATP were released into the medium by CCCP (10 microM) by 18% (N = 5), 30% (N = 5), and 88% (N = 5) for amlodipine, mibefradil, and verapamil, respectively. Thus, amlodipine, mibefradil, and verapamil, but not nitrendipine, accumulate in catecholamine storage vesicles in response to delta mu H+ generated by the endogenous V-type H(+)-ATPase, and are partially released by de-energetisation. Hence, these calcium antagonists can reach unexpectedly high concentrations in certain target cells, and give pharmacodynamic properties not shared by nitrendipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10810446&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effects of antihypertensive agents on the survival rate of polycystic kidney disease in Han:SPRD rats.

Kanno Y, Okada H, Moriwaki K, Nagao S, Takahashi H, Suzuki H.

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

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder in humans. Hypertension is one of the major complications, and its control might affect the renal survival and disease mortality. Suitable antihypertensive agents have been discussed based on clinical and animal studies, but no definitive conclusion has been reached. Generally, therefore, all antihypertensives are indiscriminately treated as if providing the same level of blood pressure control. In this study, the blood pressure control of two antihypertensives was investigated using a rat model of ADPKD in humans. Twenty-four male Hannover-Sprague Dawley (Han:SPRD) rats were divided into three groups: a group receiving amlodipine (6 mg/day), a group receiving benazepril (6 mg/day) and an untreated control group. Blood pressure, body weight, and urinary protein excretion were regularly measured up to week 52. Amlodipine and benazepril significantly decreased blood pressure and urinary protein excretion to the same degree. Moreover, a remarkably prolonged survival rate was observed in both groups (at week 52, the survival rate was 25% in controls, 50% in the amlodipine group, and 50% in the benazepril group). Examination at autopsy revealed that enlarged cysts were prevalent in the renal tissue of both experimental all three groups, suggesting that the cystic disease had reached the end-stage in all the animals. In conclusion, both amlodipine and benazepril significantly improved blood pressure control, urinary protein excretion, and survival rate, possibly due to their enhancement of renal survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12484519&dopt=Abstract amlodipine Norvasc