amlodipine Norvasc
Effects of amlodipine and lacidipine on cardiac remodelling and renin production in salt-loaded stroke-prone hypertensive rats.

Kyselovic J, Krenek P, Wibo M, Godfraind T.

Laboratoire de Pharmacologie, Universite Catholique de Louvain, Avenue Hippocrate 54, B 1200 Brussels, Belgium.

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure. 3. The lowest dosages of both drugs had non-significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt-loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor-beta1. 4. The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine. 5. Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. 6. We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11724758&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparison of L-type and mixed L- and T-type calcium channel blockers on kidney injury caused by deoxycorticosterone-salt hypertension in rats.

Baylis C, Qiu C, Engels K.

Department of Physiology, West Virginia University Health Sciences Center, Morgantown, WV 26506-9229, USA. cbaylis wvu.edu

The efficiency of calcium channel blockers (CCBs) in the treatment of chronic renal disease (CRD) is controversial. In this study, we investigated whether combined T- and L-type CCBs, using mibefradil (30 mg/kg/d), provided superior protection versus traditional L-type voltage-gated CCBs, using amlodipine (10 mg/kg/d), in the deoxycorticosterone acetate (DOCA)-salt model of high glomerular blood pressure (P(GC)) and rapidly developing kidney damage. After 4 to 5 weeks of DOCA-salt, amlodipine did not reduce proteinuria (protein, 341 +/- 90 versus 482 +/- 54 mg/24 h; P = not significant) or degree of glomerular damage (20% +/- 4% versus 28% +/- 6% damaged glomeruli; P = not significant) compared with untreated rats. Conversely, mibefradil reduced proteinuria and glomerular damage versus untreated DOCA-salt rats (protein, 244 +/- 75 mg/24 h; P < 0.02; damaged glomeruli, 11% +/- 3%; P < 0.05). Both CCBs had similar antihypertensive actions, returning blood pressure to the untreated sham value. Of note, P(GC) also was reduced by a similar extent (and to the sham value) with both mibefradil (58 +/- 2 mm Hg; P < 0.001) and amlodipine (61 +/- 2 mm Hg; P < 0.005) versus untreated DOCA-salt rats (70 +/- 1 mm Hg). This study shows that combined T- and L-type CCBs provide superior protection against CRD in the DOCA-salt model compared with L-type CCBs alone. However, this protection was not hemodynamic because similar systemic and glomerular antihypertensive responses occurred with both mibefradil and amlodipine. Although mibefradil was withdrawn from the market because of adverse drug interactions not associated with CCBs, other mixed channel blockers may provide an alternative or adjunctive therapy to angiotensin-converting enzyme inhibition in CRD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11728963&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Diverse effects of chronic treatment with losartan, fosinopril, and amlodipine on apoptosis, angiotensin II in the left ventricle of hypertensive rats.

Yu G, Liang X, Xie X, Su M, Zhao S.

Department of Geriatric Cardiology, Xiangya Hospital, Hunan Medical University, 410008, ChangSha, PR China. y9620615 public.cs.hn.cn

This study was designed to investigate diverse effects of angiotensin II (AngII) type I receptor antagonists, losartan, angiotensin converting enzyme (ACE) inhibitors, fosinopril, and calcium channel blockade, amlodipine on cardiomyocyte apoptosis and AngII in the left ventricle of spontaneously hypertensive rats (SHR). The SHRs were randomized to four groups: SHR-L (treated with losartan, 30 mg x kg(-1) x d(-1)), SHR-F (with fosinopril, 10 mg x kg(-1) x d(-1)), SHR-A (with amlodipine, 10 mg x kg(-1) x d(-1)) and SHR-C (with placebo). The cardiomyocyte apoptosis was examined by in situ TDT-mediated dUTP nick end labeling, AngII concentrations of plasma and myocardium were measured by radio immunoassay at 8 and 16 weeks of the study respectively. The results showed that: (1) compared with SHR-C at 8 and 16 weeks respectively; the systolic blood pressure was decreased similarly in the three treatment groups. Left ventricular weight and mass indexes were reduced in the three treatment groups. The latter parameter at 16 weeks was lower in SHR-F than that in the other two treatment groups. (2) Compared with SHR-C, the cardiomyocyte apoptotic index (APOI) was reduced significantly at 8 weeks only in SHR-F, and at 16 weeks in all three treatment groups. The APOI of SHR-F was lowest among the three treatment groups examined at latter endpoint. (3) Compared with SHR-C at both endpoints of this study, plasma and myocardium AngII levels were increased in SHR-L. However, plasma AngII concentrations were not altered in SHR-F and SHR-A, myocardium AngII concentrations were reduced significantly at 8 weeks only in SHR-F, and at 16 weeks in SHR-F and SHR-A. Meanwhile, myocardium AngII in SHR-F at 16 weeks was lower than that in SHR-A. The results of this study indicate that losartan, fosinopril, and amlodipine each effectively reverses heart hypertrophy and inhibits cardiomyocyte apoptosis, and fosinopril may be most effective in these cardioprotective effects. These findings suggest that the effects of the three blockers on myocardiocyte apoptosis and left ventricular hypertrophy were related to inhibition of the myocardium rennin-angiotensin-aldsterone system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11744126&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Paradoxical release of nitric oxide by an L-type calcium channel antagonist, the R+ enantiomer of amlodipine.

Zhang XP, Loke KE, Mital S, Chahwala S, Hintze TH.

Department of Physiology, New York Medical College, Valhalla, New York 10595, USA.

Amlodipine is a mixture of two enantiomers, one having L-type channel blocking activity (S-) and the other about 1,000-fold weaker activity and of little known other activity (R+). To determine whether the R+ enantiomer releases nitric oxide, the ability of amlodipine, its enantiomers, and nitrendipine to release nitric oxide in isolated coronary microvessels and to regulate cardiac tissue oxygen consumption via nitric oxide release was studied in vitro. Amlodipine and the R+ enantiomer released nitric oxide in a concentration-dependent fashion, increasing nitrite release from coronary microvessels by 57 +/- 12 and 45 +/- 5 pmol/mg/20 min at 10(-6) M (p < 0.05 from control). Nitrite release was entirely blocked by N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and HOE-140, a B2-kinin receptor antagonist. The S- enantiomer had no effect on nitrite release at any concentration. Amlodipine and the R+ enantiomer also reduced oxygen consumption in canine cardiac tissue in vitro and this was in an L-NAME-blockable manner. The S- enantiomer of amlodipine had no effect. This study shows that the R+ enantiomer of amlodipine is responsible for the release of nitric oxide and not the S- enantiomer (the L-type calcium channel blocking portion of amlodipine). Interestingly, nitric oxide release is dependent on the production of kinins because it is blocked by HOE-140. This study defines a potentially important property by which calcium channel blockers may release nitric oxide and may contribute to their use in the treatment of cardiovascular disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11791006&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Dual mechanism of action of amlodipine in human vascular smooth muscle cells.

Stepien O, Zhang Y, Zhu D, Marche P.

Department of Pharmacology, CNRS UMR 8604 and University Rene Descartes, Paris, France.

OBJECTIVES: It has been recently shown that calcium channel blockers (CCBs) could also control smooth muscle cell (SMC) growth/reactivity through mechanisms that were unrelated to their CCB property. Here, we investigated the effects of amlodipine and isradipine on Ca2+ movements and p42/p44 mitogen-activated protein kinase (ERK 1/2) activities, which are two early signalling events triggered by growth factors such as thrombin and basic fibroblast growth factor (bFGF). METHODS: In cultured human SMCs isolated from internal mammary arteries, Ca2+ movements and ERK 1/2 activation were studied by measurement of the intracellular Ca2+ concentration in Fura 2-labelled SMCs and by Western blots, respectively. RESULTS: In thrombin- and thapsigargin-stimulated SMCs, amlodipine and not isradipine dose-dependently reduced Ca2+ mobilization (i.e. Ca2+ release from internal stores); these dihydropyridines did not affect either Ca2+ influx or ERK 1/2 activation. In bFGF-stimulated SMCs, amlodipine and isradipine reduced both Ca2+ influx and ERK 1/2 activation without affecting Ca2+ mobilization. ERK 1/2 activation could also be directly stimulated by the l-type channel agonist Bay K 8644, demonstrating the involvement of voltage-gated Ca2+ influx in this process. Most of the observed effects described were obtained with approximately 10 nmol/l amlodipine/isradipine (i.e. concentrations close to the peak plasma level in treated patients). CONCLUSIONS: In human SMCs, amlodipine can (i) specifically alter Ca2+ mobilization, likely by interacting with the sarcoplasmic reticulum and (ii) inhibit voltage-dependent Ca2+ influx and the resulting ERK 1/2 activation. It is likely that amlodipine exerts its growth-inhibitory potency by interfering with multiple branches of mitogenic signalling pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11791031&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Synergistic effect of nicorandil and amlodipine on mitochondrial function during isoproterenol-induced myocardial infarction in rats.

Sathish V, Vimal V, Ebenezar KK, Devaki T.

Department of Biochemistry and Molecular Biology, University of Madras, Chennai, India.

The synergistic effects of nicorandil (KATP-channel opener) and amlodipine (calcium-channel blocker) on heart mitochondrial enzymes and the mitochondrial antioxidant defence system was examined on isoproterenol-induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg(-1) daily, i.p.) for two days showed significant changes in marker enzymes, mitochondrial enzymes and the mitochondrial defence system. Pre-co-treatment with nicorandil (2.5 mg kg(-1) daily, p.o.) and amlodipine (5.0 mg kg(-1) daily, p.o.) for 3 days significantly prevented these alterations and restored enzyme activity to near normal. These findings demonstrate the protective and synergistic effect of nicorandil and amlodipine in combination against isoproterenol-induced cardiac damage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11829124&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Randomized Placebo-Controlled Withdrawal Study of Amlodipine in Agina Pectoris.

Gorwit J, Haidet GC, Russell DC, Tonkon M, Deedwania PC, Borer JS.

Escondido Cardiology Associates, Inc, Escondido, CA, USA.

OBJECTIVES: To assess the antianginal and antiischemic efficacy, safety, and the potential for tolerance or withdrawal effects of amlodipine. BACKGROUND: The slow onset of action and long half-life of amlodipine may help avoid withdrawal effects such as the exacerbation of angina and precipitation of myocardial seen with beta-blockers. METHODS: After a 2-week single-blind placebo run-in period, 226 patients with stable exertional angina pectoris were given amlodipine (starting at 5 mg day(minus sign1) and titrated to 10 mg day(minus sign1)) in a single-blind fashion for 8 weeks. One hundred seventy-two responders (greater-than-or-equal7% improvement in symptom-limited exercise time) entered a 4-week double-blind withdrawal phase and randomly received continued treatment with amlodipine (n = 91) or placebo (n = 81). RESULTS: Treatment with amlodipine increased the exercise capacity by 14% and improved time to angina onset by 25% and time to 1-mm ST segment deviation by 18%. These variables remained essentially unchanged at the end of the 4-week withdrawal phase for the group continued on amlodipine (+0.8%, +3.2%, and +2.0%, respectively) but decreased for the group on placebo (minus sign5.8%, minus sign9.8%, and minus sign11.0%, respectively) (p < 0.001 between groups, all assessments) to values similar to those obtained during the initial placebo run-in period. Approximately one-third of the patients responded to 5 mg amlodipine during single-blind therapy and according to "usual clinical practice" remained on this dose. The results of randomized withdrawal in the subgroup receiving 5 mg also favored amlodipine over placebo. Side effects were reported by 47% of patients on amlodipine and by 22% of patients receiving placebo. The most frequently reported side effects for

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850645&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Analysis of amlodipine in human plasma by liquid chromatography-mass spectrometry.

Feng Y, Zhang L, Shen Z, Pan F, Zhang Z.

Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, People's Republic of China. purplefeng2000 yahoo.com

A simple, sensitive, and specific liquid chromatographic method coupled with electrospray ionization (ESI)-mass spectrometry for the determination of amlodipine is developed. After extraction by ethyl acetate using nicardipine as the internal standard, solutes are separated on a C18 column with a mobile phase of methanol-1% HAc (65:35). Detection is performed on an air pressure ionization single quadruple mass spectrometer equipped with an ESI interface and operated in positive-ionization mode. Amlodipine quantitation is realized by computing the peak-area ratio (amlodipine-nicardipine) of the extracts analyzed in single ion monitoring mode (m/z 431 and m/z 480 for amlodipine and nicardipine, respectively) and comparing them with the calibration curve (r = 0.9991).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11866387&dopt=Abstract amlodipine Norvasc