amlodipine Norvasc
Slow dissociation of long-acting Ca2+ antagonist amlodipine from 3H-PN200-110 binding sites in membranes of rat hearts and brains.

Sugiyama K, Qu YL, Maruyama K, Hattori K, Watanabe K, Nagatomo T.

Department of Pharmacology, Niigata College of Pharmacy, Japan.

The dissociation rate of amlodipine ((+/-)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl- 3,5- pyridinedicarboxylate benzenesulfonate) from rat heart and brain membranes preincubated with drugs and washed out with buffer was assessed by radioligand binding assay using 3H-PN200-110 as a radioligand. The remaining KCl-induced contraction in rat aortic strips washed out after treatment with this drug and the pKi (inhibition constant) values of the drug were compared with those of nisoldipine, nifedipine, manidipine and benidipine. The inhibition of 3H-PN200-110 binding induced by nifedipine was reversed by washing, whereas that induced by amlodipine, manidipine, and benidipine was not readily reversed under these conditions. When rat aortic strips were pretreated with Ca2+ antagonists, the rank order of the inhibition of contractions induced by 50 mM KCl was manidipine = benidipine > amlodipine > nisoldipine > nifedipine, even though Ca2+ antagonists were not present in the extracellular medium. The pKi values of amlodipine in the heart and brain were 6.86 and 7.41, respectively, and these values were lower than those of the other Ca2+ antagonists. There was a good correlation between the potency of the inhibition of 3H-PN200-110 binding by drugs after the washout of membranes and the inhibition exerted by the drugs in contractions induced by 50 mM KCl after the washout of tissues, although this residual inhibition was not correlated with pKi values. Thus, these results suggest that amlodipine has a very slow rate of dissociation from 3H-PN200-110 binding sites, as do manidipine and benidipine, and this property may explain its long-lasting antihypertensive effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8850304&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Hemodynamic and 24-h blood pressure profile of amlodipine monotherapy.

Ibrahim MM, el-Boghdadly B, Zaghloul SS.

Cardiology Department and Diagnostic Ultrasound Laboratory, Cairo University, Egypt.

OBJECTIVES: To test the therapeutic efficacy, hemodynamic profile, changes in arterial compliance, left ventricular mass and side effects of amlodipine monotherapy in hypertensive Egyptians. BACKGROUND: Amlodipine is a dihydropyridine calcium antagonist with prolonged duration of action. Its hemodynamic and hypotensive effects were not reported in hypertensive Egyptians. Hypertension is a major health problem in Egypt. Racial differences in hypotensive efficacy of some drugs have been described. METHODS: Thirty-two hypertensive patients in stages I and II WHO were recruited from a hypertension clinic. Following 2-4 weeks placebo period 23 patients satisfied inclusion criteria of DBP 95-115 mm Hg. Active amlodipine therapy 5-10 mg was given once daily. Office BP was measured at monthly intervals for 3 months. Ambulatory 24-h blood pressure (ABP) and echo-Doppler studies were performed at the end of placebo and after amlodipine therapy. RESULTS: Twenty patients completed the 3 months active treatment period, their age ranged from 30-63 years; 13 were males, body mass index (BMI) was 31 +/- 14 kg/m2 (mean +/- s.d.). Office systolic (S) BP decreased from 152 +/- 14 to 133 +/- 8 mm Hg, diastolic (D) BP from 104 +/- 6 to 89 +/- 8 mm Hg, BP was normalised ( < 140/90 mm Hg) in 13 patients. Heart rate did not change. ABP 24 h, day-time, night time and early morning readings decreased significantly. Amlodipine attenuated SBP rises ( > 140 mm Hg) from 62% to 28% (P < 0.001) and DBP ( > 90 mm Hg) from 73% to 46% (P < 0.001). Cardiac index and left ventricle (LV) functional shortening did not change while systemic vascular resistance decreased from 35 to 29.8 units (P < 0.001). LV mass index decreased from 101 to 96 gm/m2 (NS) and arterial compliance increased from 0.97 to 0.99 ml/mm Hg (NS). Oedema of lower limbs developed in six patients and was the only side effect. CONCLUSION: Amlodipine effectively lowered BP when given as monotherapy to hypertensive Egyptians. It did not influence heart rate, cardiac index or myocardial contractility. Change in LV mass and arterial compliance were not significant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8880565&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of amlodipine on renin secretion and renin gene expression in rats.

Schricker K, Hamann M, Macher A, Kramer BK, Kaissling B, Kurtz A.

Physiologisches Institut, Universitat Regensburg, Germany.

1. This study was done to characterize the influence of calcium channel blockade on renin secretion and renin gene expression in normal rats and rats with renovascular hypertension. To this end we studied the effects of the 1,4-dihydropyridine derivative, amlodipine, on plasma renin activity and renal renin m-RNA levels in normal rats and rats with unilateral renal hypoperfusion induced by applying 0.2 mm left renal artery clips over four days. 2. In normotensive rats, amlodipine significantly decreased basal blood pressure by about 20 mmHg when applied in a concentration of 5, 15 and 45 mg kg-1. Plasma renin activity and also renin mRNA levels were not changed after application of 5 mg kg-1 of amlodipine. However, at a concentration of 15 or 45 mg kg-1, amlodipine, significantly increased not only plasma renin activity by about 250% and 300%, but also renin mRNA levels by about 100% and 500%. The action of amlodipine on all these parameters was maximal after 24 h. Treatment with amlodipine in a concentration of 15 mg kg-1 also increased renin immunoreactive areas in the kidney cortex by retrograde recruitment of renin expressing cells in the afferent arterioles. 3. In 2kidney-1 clip rats, systolic blood pressure rose continuously whilst plasma renin activity and renin m-RNA in the clipped kidney increased transiently and renin m-RNA in the contralateral kidney was constantly suppressed. Amlodipine at a concentration of 15 mg kg-1 markedly attenuated the increase of blood pressure in 2kidney-1 clip rats, produced an almost additive effect on plasma renin activity and showed a tendency to increase renin m-RNA levels in the clipped kidneys. Renin m-RNA levels in the contralateral kidney were also significantly suppressed in the animals receiving additional treatment with amlodipine. 4. These findings suggest that inhibition of calcium channels by amlodipine stimulates renin secretion and renin gene expression in vivo. These stimulatory effects are almost additive to the changes of renin secretion occurring after an unilateral fall of renal perfusion pressure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8904650&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Delay by a calcium antagonist, amlodipine, of the onset of primary ventricular fibrillation in myocardial ischemia.

Timour Q, Bui-Xuan B, Faucon G, Aupetit JF.

Department of Medical Pharmacology, Cl. Bernard University, Lyon, France.

Calcium antagonists have been reported to counteract the increase by ischemia of vulnerability to ventricular fibrillation. This ability might be especially of interest in the prevention of sudden death subsequent to a major, but transitory, inadequacy between myocardial oxygen requirements and available coronary blood flow produced by exercise, emotion, etc., because death is then not related to irreversible damage of myocardial fibers. This study has been undertaken to examine the protective effect of a calcium antagonist on an animal model of this type of ischemia. This model used complete, but transient occlusion of the left anterior descending coronary artery near its origin during pacing at a constant high rate (180 beats/min) in anesthetized, open-chest pigs, most often resulting in fibrillation within 1-2 minutes after a progressive fall of the electrical fibrillation threshold. Amlodipine was the preferred calcium antagonist for this study because it is only moderately negatively inotropic. The results of the preventive administration of amlodipine was assessed by the time to onset of fibrillation. Amlodipine 0.30 mg/kg prolonged this time by 50-100% (p < 0.05) without appreciable impairment of blood pressure or myocardial contractility. Concurrently, amlodipine delayed the shortening of the monophasic action potential duration, the lengthening of conduction time, and the alterations of ST segments and T waves linked to ischemic depolarization. Consequently, when given experimentally before the occurrence of major, but transitory ischemia, amlodipine protected against fibrillation. Similarly, in clinical settings it ought to delay sudden death that may occur as a result of a major but transitory inadequacy between myocardial oxygen requirements and available coronary blood flow.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8924058&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Coupled-column chromatography on a Chiral-AGP phase for determination of amlodipine enantiomers in human plasma: an HPLC assay with electrochemical detection.

Josefsson M, Norlander B.

Department of Clinical Pharmacology, Faculty of Health Sciences, Linkoping University, Sweden.

A sensitive enantioselective high performance liquid chromatographic assay for determination of the dihydropyridine-type calcium antagonist amlodipine in human plasma samples is described. Chiral chromatography is performed on an alpha 1-acid glycoprotein column (i.e. Chiral-AGP) and the eluted enantiomers are trapped and compressed on two short columns before final achiral chromatography on a narrow bore column (i.e. Zorbax SB-Ph) using electrochemical detection. Both stereoselective quantitative analysis and enantiomeric ratio analysis, for samples with a known total concentration of amlodipine are described. The quantitative assay shows linearity over the range 0.5-10 ng ml-1 for the two enantiomers and the limit of detection is about 0.2 ng ml-1. The method has been applied to a pharmacokinetic study of the enantiomers of amlodipine in human subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8933429&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Different effects of calcium antagonists, nitrates, and beta-blockers on platelet function. Possible importance for the treatment of unstable angina.

Knight CJ, Panesar M, Wilson DJ, Chronos NA, Patel D, Fox K, Goodall AH.

Department of Cardiology, Royal Brompton Hospital, London, UK.

BACKGROUND: The three major classes of antianginal drug all inhibit platelet aggregation at high concentrations in vitro, but detecting clinically relevant effects has proved to be more difficult. We used whole-blood flow cytometry, a sensitive method that allows direct measurement of activation antigens on the surface of individual platelets in whole unfixed blood, to evaluate the effect of representative antianginal drugs on platelet function in vivo in healthy volunteers. METHODS AND RESULTS: The effects of glyceryl trinitrate (GTN), amlodipine, and atenolol were studied in nine normal volunteers. Fibrinogen binding to activated GP IIb/IIIa and expression of P-selectin, GP Ib, and GP IIb/IIIa on the platelet surface were measured. In addition, fibrinogen binding and P-selectin expression were measured in response to ex vivo stimulation with the agonists ADP and thrombin. The three drugs had very different effects on platelets. GTN inhibited platelet fibrinogen binding and expression of P-selectin at rest and in response to agonist stimulation, whereas amlodipine enhanced P-selectin expression and atenolol increased fibrinogen binding in response to agonists. Atenolol did not block the stimulatory effects of epinephrine on ADP-induced platelet activation. GTN neutralized the proactivatory effects of amlodipine, whereas the effects of atenolol and amlodipine were not additive. CONCLUSIONS: The three main classes of antianginal medication have different and possible clinically relevant effects on platelet behavior in vivo, nitrates causing inhibition of aggregation (fibrinogen binding) and degranulation (P-selectin expression), calcium antagonists enhancing degranulation, and beta-blockers enhancing aggregation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8994427&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production.

Wang WZ, Matsumori A, Yamada T, Shioi T, Okada I, Matsui S, Sato Y, Suzuki H, Shiota K, Sasayama S.

Department of Cardiovascular Medicine, Kyoto University, Japan.

BACKGROUND: Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV). METHODS AND RESULTS: Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight-to-body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (P < .01, P < .05, and P < .05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore, NG-monomethyl-L-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (P < .01). CONCLUSIONS: Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8994443&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Effect of the calcium antagonist amlodipine on non-vascular smooth muscle exemplified by the uterus]

[Article in German]

Lechner W, Bergant A, Solder E, Kolle D.

Universitatsklinik fur Frauenheilkunde, Innsbruck.

The effect of amlodipine, a recently developed calciumantagonist on 21 uterine strips was investigated. Uterine activity, expressed by the area under the curve was depressed from 504 (51 to 1056) mm2 to 0 (0 to 130) 10 min after the application of amlodipine. After 20 and 60 min, the values were 0 (0 to 1310) and 0 (0 to 317) (median, 10th and 90th percentile). The decrease of uterine activity was highly significant (p < 0.0001). In summary, amlodipine exhibits a prompt and excellent relaxation on the spontaneous contractions of uterine strips.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9045529&dopt=Abstract amlodipine Norvasc