amlodipine Norvasc
Possible prevention by amlodipine of ventricular fibrillation related to brief ischemia episodes.

Timour Q, Aupetit JF, Freysz M, Frassati D, Faucon G.

Departement de pharmacologie medicale, Universite Claude Bernard, Lyon, France.

Calcium antagonists may reduce propensity to ventricular fibrillation, by altering the balance between coronary blood flow and metabolic demand, and thus may substantially prolong time to occurrence of fibrillations. This delay in the onset of fibrillation should be sufficient to prevent sudden death in the case of transitory episodes of myocardial ischemia. Therefore, this study was based on the determination of time to onset of fibrillation in an animal model of transitory ischemia. This model was achieved by the complete, but transitory occlusion of the left anterior descending coronary artery near its origin under ventricular pacing at a constant high rate (180 beats/min), in anesthetized, open-chest pigs. Amlodipine was preferred to another calcium antagonist for this study because it is among the least negatively inotropic of these drugs. It was intravenously infused at 0.02 mg.kg-1.min-1. Time to fibrillation was prolonged from 87 +/- 10 to 146 +/- 16 s (p < 0.05) with the 0.30 mg/kg dose and to 201 +/- 22 s (p < 0.05) with the 0.60 mg/kg dose, without serious impairment of blood pressure or left ventricular dP/dtmax in the absence of ischemia. Concurrently, amlodipine significantly limited the shortening of monophasic action potential duration (200 +/- 4 vs. 172 +/- 6 ms), the lengthening of conduction time (43 +/- 2 vs. 53 +/- 2 ms), and the alterations of ST segments and T waves induced by 60 s ischemic depolarization. Consequently, amlodipine might reduce the incidence of sudden death by lengthening time to onset of fibrillation beyond the duration of the ischemia, when transitory.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9047040&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Clinical study of the month. Which initial antihypertensive? Results from the ALLHAT trial]

[Article in French]

Scheen AJ, Krzesinski JM.

Service de Diabetologie, Nutrition et Maladies metaboliques, Service de Medecine interne generale, Departement de Medecine, CHU Ourthe-Ambleve.

Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is still controversial. The "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) should give such an answer. It is a randomised, double-blind, trial designed to determine whether treatment with either a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic. A total of 33,357 participants aged 55 years or older with mild to moderate hypertension and at least 1 other CHD risk factor were randomly assigned to receive chlorthalidone (12.5 to 25 mg/day; n = 15,255), amlodipine (2.5 to 10 mg/day; n = 9,048) or lisinopril (10 to 40 mg; n = 9,054). The primary outcome combined both fatal CHD and non-fatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-causes mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure and peripheral arterial disease). Chlorthalidone was slightly more effective in reducing systolic pressure while amlodipine reduced slightly more effectively diastolic blood pressure. After a mean follow up of 4.9 years, no differences were observed between the three treatments regarding both the primary outcome and the total mortality. Secondary outcomes were similar when comparing amlodipine vs chlorthalidone. A moderately higher 6-year incidence rate of clinically detected heart failure was observed with amlodipine, but without significant influence on mortality. For lisinopril vs chlorthalidone, lisinopril had slightly higher 6-year rates of combined CVD, stroke and heart failure. In conclusion, thiazide-type diuretics are superior in preventing one or more major forms of CVD and offer the advantage to be cheaper. They should be preferred for first-step antihypertensive therapy. However, to reach the recommended blood pressure target, most patients should receive a combination of antihypertensive compounds. Such a combination should always comprise a diuretic agent, in absence of contra-indications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12647599&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of the dihydropyridine calcium channel blocker amlodipine on ventricular and atrial protein synthesis in an aortic constriction model of hypertension and, following chronic treatment, in the left ventricle of SHR rats.

Patel VB, Siddiq T, Sherwood R, Richardson PJ, Preedy VR.

Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, London, UK.

The dihydropyridine calcium channel blocking agent amlodipine is an effective anti-hypertensive agent and its use (in doses of 5 or 10 mg/day/kg body weight) was investigated in male Wistar rats with hypertension induced by aortic constriction. Controls were sham-operated and pair-fed. At the end of the study, rates of protein synthesis were measured with radiolabelled phenylalanine to calculate fractional rates of protein synthesis (ks), absolute rates of protein synthesis (Vs) and synthesis rates relative to RNA (kRNA). After 30 days of aortic constriction, weights of the left ventricle and left atrium were significantly increased by hypertension. The weights of the right ventricle and right atrium were relatively unaffected. Hypertension was accompanied by significant increases in the protein and RNA contents of the left ventricle and left atrium. The contractile and non-contractile protein contents were also increased in the left ventricles of hypertensive rats as were total proteins and total RNA. In the myofibrillary fraction, ks decreased. The right ventricle and right atrium were generally unaffected except for a decline in mixed protein ks. Many of these changes in hypertension were ameliorated by treatment with amlodipine, particularly at the higher dose (i.e. 10 mg/kg body weight/day) implicating an effect on protein metabolism. In the left ventricle these included amelioration of the increases in mixed and contractile proteins, total RNA contents, mixed Vs and Vs for sarcoplasmic and stromal proteins. The ameliorating effects of amlodipine were moderate in the left atrium. Furthermore, amlodipine also retarded the hypertension-induced reduction in right ventricule rates of protein synthesis. Although the preceding study emphasises the preventative aspects of amlodipine's efficacy, an additional study was carried out in SHR rats to ascertain the applicability for regression per se. Amlodipine (10 mg/kg/body weight) therapy for 30 weeks caused regression of LV mass, total protein, RNA and DNA contents. We conclude that amlodipine, is an efficient agent in ameliorating the hypertension-induced changes in protein metabolism in an aortic constriction model.

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amlodipine Norvasc
Amlodipine and benazeprilat differently affect the responses to endothelin-1 and bradykinin in porcine ciliary arteries: effects of a low and high dose combination.

Lang MG, Zhu P, Meyer P, Noll G, Haefliger IO, Flammer J, Luscher TF.

Department of Research, University Hospital Basel, Switzerland.

PURPOSE: Visual field defects caused by vasospasm are often encountered in ophthalmology as a feature of glaucoma with poor response to conventional treatment. Combination therapy with drugs acting via different mechanisms might be more effective. Therefore, the effects of the calcium antagonist amlodipine and the angiotensin converting enzyme (ACE) inhibitor benazeprilat at low and high dose combination on contractions to endothelin-1 and endothelium-dependent relaxations to bradykinin were examined in porcine ciliary arteries. METHODS: Segments of the arteries were suspended in myographs for isometric tension recording. RESULTS: Pretreatment of the vessels with either amlodipine, the low or high dose combination significantly reduced the sensitivity to endothelin-1 as compared to control (concentration shift 18.3-fold, 14.2-fold, 23.3-fold respectively; p < 0.05), while benazeprilat was ineffective. The maximal response to endothelin-1 (10(-7) M) was most inhibited by the high dose combination which reduced the contractions by 49% as compared to control (p < 0.05). The low dose combination and amlodipine alone were less effective (reduction: 25%; p < 0.05 and 20%; n.s., respectively). On the other hand, benazeprilat enhanced the sensitivity (concentration shift 73-fold; p < 0.05) and maximal relaxation to bradykinin (by 27%; p < 0.01), whereas amlodipine or the low or high dose combination were ineffective. CONCLUSIONS: These findings indicate that amlodipine and benazeprilat differently affect vascular function of ciliary arteries. A high dose combination of both substances was most effective in inhibiting contractions to endothelin-1, suggesting a potentiating effect of the two compounds. In contrast, endothelium-dependent relaxations to bradykinin were enhanced by benazeprilat alone, but not when combined with amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9088736&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A novel benzothiazine Ca2+ channel antagonist, semotiadil, inhibits cardiac L-type Ca2+ currents.

Koidl B, Miyawaki N, Tritthart HA.

Institut fur Medizinische Physik und Biophysik, Universitat Graz, Austria. bernd.koidl kfunigraz.ac.at

The influence of semotiadil fumarate, a novel vasoselective Ca2+ channel antagonist with a benzothiazine skeleton, was measured on the high-threshold Ca2+ current ICa,L in guinea-pig ventricular myocytes prepared by coronary perfusion with collagenase solution. Patch- and voltage-clamp methods were used to measure ICa,L. Diltiazem, nifedipine and amlodipine were studied for comparison. Samotiadil could be shown to inhibit ICa,L in a dose-dependent manner in concentrations similar to those of diltiazem but was less effective than amlodipine and nifedipine. The IC50 for nifedipine and amlodipine was in the range between 0.1 and 1 microM and that of semotiadil and diltiazem was between 10 and 100 microM. Recovery from inactivation of ICa,L in the control and under the influence of nifedipine 0.01 microM) and amlodipine (0.1 microM) was complete alter I. Semotiadil (0.1 microM) and diltiazem (1 microM) prolonged the time to full recovery to 20 s. This significant delay in the recovery of ICa,L produced by semotiadil indicates a mode of action similar to that of the verapamil type of Ca2+ channel antagonists and masses a clear distinction between it and the dihydropyridines, which have no effect on the recovery process. The rate dependence of the effect in combination with a distinct influence of the holding potential underlines the use dependence of the mechanism underlying the effect of semotiadil. The well-known high vasoselectivity of semotiadil in combination with a relatively low Ca2+ channel antagonistic influence on the heart makes semotiadil an interesting candidate for the treatment of coronary heart diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9098694&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Angiotensin AT1 receptor inhibition. Effects on hypertrophic remodeling and ACE expression in rats with pressure-overload hypertrophy due to ascending aortic stenosis.

Weinberg EO, Lee MA, Weigner M, Lindpaintner K, Bishop SP, Benedict CR, Ho KK, Douglas PS, Chafizadeh E, Lorell BH.

Charles A. Dana Research Institute, Boston, Mass, USA.

BACKGROUND: We tested the hypothesis that long-term administration of the specific angiotensin II subtype 1 (AT1)-receptor blocker BMS-186295 will regress hypertrophy and modify left ventricular angiotensin converting enzyme (ACE) expression in rats with ascending aortic stenosis. METHODS AND RESULTS: Six weeks after surgery, rats with ascending aortic stenosis were randomized to receive either the AT1-receptor blocker BMS-186295 50 mg.kg-1.d-1 (n = 49), amlodipine 2.5 mg.kg-1.d-1 (n = 48) as a positive control for systemic vasodilation, or no drug (n = 48) and compared with sham-operated rats (n = 39). Drug treatment was continued for 15 weeks. Left ventricular ACE mRNA levels were measured by ribonuclease protection assay. The left ventricular/body weight ratio was increased 43% in hearts from rats with untreated left ventricular hypertrophy (LVH) versus control hearts (P < .05). However, there was no difference in either the left ventricular/body weight ratio (2.78 +/- 0.08 versus 2.81 +/- 0.20 mg/g; P = NS) or myocyte cross-sectional area in the AT1-blocker-treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertrophy. In vivo left ventricular systolic pressure was significantly higher in untreated LVH versus sham-operated rats (193 +/- 8 versus 118 +/- 4 mm Hg; P < .05), and there was a similar severe elevation of left ventricular systolic pressure in the AT1-blocker- and amlodipine-treated LVH groups (189 +/- 9 and 188 +/- 16 mm Hg; P = NS versus untreated LVH). In vivo left ventricular end-diastolic pressure was higher in the untreated LVH than in the sham-operated rats (14.8 +/- 2.3 versus 7.0 +/- 0.5 mm Hg; P < .05). Left ventricular end-diastolic pressure was lower in the AT1-blocker-treated (11.0 +/- 1.7 mm Hg) and amlodipine-treated rats (11.5 +/- 1.8 mm Hg) and was similar to left ventricular end-diastolic pressure in the sham-operated rats (P = NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but were normalized in both the AT1-blocker-treated rats and amlodipine-treated rats. CONCLUSIONS: Long-term AT1-receptor blockade did not regress LVH in rats with persistent systolic pressure overload due to ascending aortic stenosis. However, both AT1-receptor blockade and amlodipine improved in vivo left ventricular end-diastolic pressure in association with the normalization of left ventricular ACE mRNA levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9118530&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine prevents and reverses the elevation in [Ca2+]i and the impaired phagocytosis of PMNL of diabetic rats.

Seyrek N, Marcinkowski W, Smogorzewski M, Demerdash TM, Massry SG.

Division of Nephrology, University of Southern California School of Medicine, Los Angeles 90033, USA.

BACKGROUND: High glucose concentration, through the activation of calcium channels, augments in vitro calcium entry into cells and leads to elevation in the basal levels of [Ca2+]i, the latter causes cell dysfunction. DESIGN OF STUDY: The present study examined whether streptozotocin-induced diabetes mellitus in rats causes a rise in [Ca2+]i of PMNL and impairs their phagocytosis and whether treatment of these rats with the calcium channel blocker, amlodipine, prevents and/or reverses these derangements. Amlodipine was given either from day one of diabetes or after 3 or 12 days of established diabetes. RESULTS: The [Ca2+]i of PMNL was elevated and their phagocytosis was reduced after one day of diabetes. These derangements were present and became more marked with longer duration of diabetes. There was a direct and significant correlation (r = 0.88) between [Ca2+]i of PMNL and blood glucose and an inverse relationship between phagocytosis and blood glucose (r = 0.83) or [Ca2+]i (r = 0.67). Three days of amlodipine therapy were required to completely prevent or reverse the elevation in [Ca2+]i of PMNL. This action of the drug occurred despite the hyperglycaemia. Amlodipine produced marked and significant improvements in phagocytosis but the values remained modestly below normal. Amlodipine given to normal rats did not affect [Ca2+]i or phagocytosis of PMNL. CONCLUSION: The results show that (i) [Ca2+]i of PMNL increases and phagocytosis decreases rapidly after the induction of diabetes; (ii) treatment of diabetic rats with amlodipine normalizes [Ca2+]i of PMNL and markedly improves their phagocytosis, despite hyperglycemia; (iii) high [Ca2+]i is responsible, in major part, for the impaired phagocytosis but other factors are also operative; and (iv) calcium channel blockers could prove useful in the treatment of the metabolic and functional derangements of PMNL in patients with poorly controlled diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9132643&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Treatment of systemic hypertension in cats with amlodipine besylate.

Henik RA, Snyder PS, Volk LM.

Department of Medical Sciences, University of Wisconsin-Madison 53706, USA.

Amlodipine besylate, a calcium channel blocker, was used to treat (mean +/- standard deviation [SD], 127 +/- 68 days) 12 cats with systemic hypertension. Amlodipine was administered orally at a dosage of 0.625 mg per cat (range, 0.08 to 0.23 mg/kg body weight; mean dose +/- SD, 0.17 +/- 0.04 mg/kg body weight) once daily as a single agent. Average indirect systolic blood pressure measurements in the 12 cases decreased significantly from 198 to 155 mmHg during amlodipine treatment. Significant changes in body weight and serum creatinine and potassium concentrations were not detected. Amlodipine appears to be a safe and effective oral treatment for systemic hypertension in cats when used chronically once daily as a single agent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9138233&dopt=Abstract amlodipine Norvasc