amlodipine Norvasc
Biochemical components and myocardial performance after reversal of left ventricular hypertrophy in spontaneously hypertensive rats.

Arita M, Horinaka S, Frohlich ED.

Alton Ochsner Medical Foundation, New Orleans, Louisiana 70121.

OBJECTIVE: This study was undertaken to determine the biochemical and left ventricular functional changes associated with reversal of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). DESIGN: Male SHR and normotensive Wistar-Kyoto (WKY) rats, aged 19 weeks, were treated for 3 weeks with vehicle, amlodipine (10 mg/kg), benazepril (10 mg/kg) or the combination of both agents (4 mg/kg amlodipine and 4 mg/kg benazepril). Left ventricular function was assessed while blood was infused rapidly, at pharmacologically reduced and pretreatment mean arterial pressure (MAP). RESULTS: All treatments reduced MAP and left ventricular mass significantly in SHR. Myocardial protein, RNA and myocardial collagen content were reduced proportionately in all treatment groups in SHR, but not in WKY rats. DNA remained unchanged in all groups. Increased right ventricular mass was produced by amlodipine in both SHR and WKY rats (SHR +11.3%; WKY +9.8%), but this was prevented by cotreatment with benazepril. Right ventricular protein and collagen increased significantly with amlodipine in SHR but not WKY rats, and there were no changes in right ventricular RNA and DNA contents in either strain. Amlodipine improved, benazepril impaired and the combination of both agents maintained left ventricular pumping ability when pressure was increased abruptly to pretreatment levels in WKY rats. In contrast, when afterload was increased abruptly in SHR to pretreatment levels, neither amlodipine nor benazepril affected pumping ability, although it was enhanced by the combination. CONCLUSIONS: These data demonstrate that amlodipine, benazepril and their combination reduced left ventricular mass in SHR. This reversal of LVH was associated with proportional reductions in mycotic protein, RNA and collagen, but not DNA. Therefore, it seems unlikely that LVH reversal with these agents was associated with increased fibrous tissue or impaired left ventricular performance. Finally, addition of the angiotensin converting enzyme inhibitor prevents the increase in right ventricular mass produced by the calcium antagonist.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8254177&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of the calcium channel blocker amlodipine on memory in mice.

Quartermain D, Hawxhurst A, Ermita B, Puente J.

Department of Neurology, New York University Medical Center, New York 10016.

Five experiments were performed to investigate the effects of amlodipine, a calcium channel antagonist of the 1,4-dihydropyridine class, on consolidation and retrieval of memory in mice. In a single-trial passive avoidance task, amlodipine was administered pretraining, posttraining, or pretesting. Results of temporal and dose-response studies showed that memory enhancement (significant increase in step-through latency) occurred when amlodipine (5, 7, 9, 15, and 30 mg/kg) was given either immediately post-training or (15 mg/kg) 15 min pretesting. Using a conditioned emotional response task, tone was paired with shock using Pavlovian conditioning procedures. Strength of conditioning was assessed by measuring suppression of drinking in the presence of a tone. Amlodipine (7 mg/kg) given immediately following both high- and low-intensity shock significantly enhanced conditioned suppression. In the third experiment thirsty mice were trained on a spatial discrimination task in a linear maze. Correct choices were reinforced with liquid reinforcement. Amlodipine (10 mg/kg) injected immediately after the training session produced a significant enhancement of discrimination performance on a 24-h retention test. In the fourth experiment mice were given 25 training trials in a two-way active avoidance task and were treated with either amlodipine (10 mg/kg) or saline after training. Amlodipine-treated mice made significantly more avoidances on the test session than control animals. The final experiment demonstrated that the deficit in approach-avoidance behavior seen in 18-month-old mice could be reversed by amlodipine treatment after the training session. These studies suggest that amlodipine can facilitate memory consolidation and retrieval.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8297317&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Safety and efficacy of amlodipine. A new once-daily calcium antagonist in non-hypertensive patients with coronary artery disease.

Ogawa T, Yasui K, Tomizawa T, Sugishita Y.

Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Japan.

To analyze the effects of the treatment of 5 mg amlodipine on blood pressure and heart rate with a 24-hour ambulatory blood pressure monitoring device and to evaluate its antiischemic efficacy using treadmill exercise testing, 7 non-hypertensive patients with coronary artery disease were studied. The systolic and diastolic blood pressure and heart rate recorded over the entire day and during daytime did not change significantly after the treatment. On the other hand, the systolic blood pressure decreased significantly at night (122 +/- 19-->113 +/- 17 mmHg, p < 0.05) after treatment, but the change can be considered to be within the physiological range. Exercise duration increased significantly after the administration of amlodipine (9.7 +/- 4.8-->11.1 +/- 4.9 min, p < 0.05). Systolic blood pressure, heart rate and rate-pressure product decreased significantly and in addition, ST segment depression was significantly less marked (-0.25 +/- 0.09-->-0.21 +/- 0.09 mV, p < 0.05) after treatment, when compared at the same level of work load. Therefore, the new once-daily calcium antagonist amlodipine is safe and efficacious in non-hypertensive patients with coronary artery disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8301842&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
An overview of the pharmacokinetics and pharmacodynamics of amlodipine in elderly persons with systemic hypertension.

Abernethy DR.

Brown University, Department of Medicine, Rhode Island Hospital, Providence 02903.

Pharmacokinetic and pharmacodynamic data were compared between elderly and young patients with hypertension who received single intravenous doses of amlodipine, a dihydropyridine calcium antagonist, followed by oral administration of amlodipine up to 10 mg once daily for 12 weeks. After intravenous administration, elderly patients had prolonged elimination half-life values (58 +/- 11 vs 42 +/- 8 hr; p < 0.05) caused by decreased clearance (19 +/- 5 vs 7 liters/hr; p < 0.05). Systolic and diastolic blood pressures were significantly decreased from baseline throughout the 3-month treatment period in both groups. After long-term oral administration, elderly and young patients had comparable decreases in mean blood pressure at a given drug plasma concentration. The antihypertensive effect of amlodipine is well correlated with plasma concentration and, at a given concentration, is similar in both elderly and young patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8310971&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine reduces graft coronary artery disease in rat heterotopic cardiac allografts.

Atkinson JB, Wudel JH, Hoff SJ, Stewart JR, Frist WH.

Department of Pathology, Vanderbilt University, Nashville, TN 37232.

The long-acting dihydropyridine calcium antagonist, amlodipine, suppresses atherogenesis in experimental animals. To determine the effect of amlodipine on allograft coronary artery disease in the transplanted heart, we used a working heterotopic rat heart transplant model. All rats were immunosuppressed with cyclosporine as a single agent and randomized to a control group (n = 9) and an amlodipine-treated group (n = 9). After 90 days, rats were killed, and the extent of graft coronary artery disease was assessed by digitizing morphometry. No significant differences were noted for mean arterial blood pressure or serum total cholesterol, high-density lipoprotein cholesterol, or triglycerides at the time of death. Amlodipine was associated with significantly less narrowing in the coronary arteries (mean percent narrowing for control group, 48.9% +/- 8.2%; mean percent narrowing for amlodipine group, 25.5% +/- 9.9%; P < 0.05). These findings suggest a role for calcium channel blockers in the prevention of graft coronary artery disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8312305&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Chronopharmacology of amlodipine in rats.

Fujimura A, Shiga T, Ohashi K, Ebihara A.

Department of Clinical Pharmacology, Jichi Medical School Tochigi, Japan.

The present study was undertaken to examine whether plasma concentrations of amlodipine, a calcium antagonist, and its diuretic effects vary with the time of dosage. Pharmacokinetic study; 20 mg/kg of amlodipine was given orally to rats at 10 am (day trial) or 10 pm (night trial), and blood samples were obtained during a 24-hour period. Pharmacodynamic study; two doses (10 and 20 mg/kg) of amlodipine were given orally at 10 am or 10 pm by a cross-over design, and urine was collected for 12 hours after dosage. Rats were maintained under condition of light from 7 am to 7 pm. The following results were obtained; The tmax of amlodipine was shorter and the Cmax was greater in the night trial than in the day trial. Its diuretic effects were greater in the night trial. These results suggest that the pharmacokinetic and pharmacodynamic profiles of amlodipine vary with its time of dosage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8350673&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension.

de Courten M, Ferrari P, Schneider M, Bohlen L, Shaw S, Riesen W, Heynen G, Weidmann P.

Medizinische Poliklinik, University of Berne, Switzerland.

To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage. At entry (before placebo), SI was slightly but not significantly lower in group A than B [2.7 vs. 3.6 x 10(-4) ml.microU-4.min-1]; fasting plasma insulin was 13.6 vs. 12.9 microU.ml-1. After 6 weeks on placebo, S1 averaged 3.7 in group A and 4.4 x 10(-4) microU.ml-1.min-1 in group B; fasting plasma insulin was 14.6 vs. 15.1 microU.ml-1, and glucose 5.5 vs. 5.5 mmol.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8359183&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The action of amlodipine on voltage-operated calcium channels in vascular smooth muscle.

Hughes AD, Wijetunge S.

Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London.

1. Amlodipine, a dihydropyridine derivative largely ionized at physiological pH, inhibited calcium channel currents in single vascular smooth muscle cells isolated from rabbit ear artery in a concentration-dependent manner. 2. Amlodipine inhibited the current-voltage relationship for calcium channel currents across the range of test potentials used. However, the effect of amlodipine was more marked on more depolarized test potentials. Amlodipine also shifted the steady-state inactivation curve for calcium channel currents in a hyperpolarized direction. 3. The potency of amlodipine as determined from the steady-state inhibition of calcium channel current induced by the drug was dependent on the holding potential of the cells. Use of a more depolarized holding potential increased the potency of amlodipine. 4. Onset of amlodipine-induced inhibition was relatively rapid at both -60 mV and -40 mV holding potential. The use of a more depolarized holding potential increased the rate of association of amlodipine. No recovery from amlodipine-induced inhibition was seen over a 20 min period following washout of the drug. 5. In addition to voltage-dependence, the action of amlodipine showed use-dependence, in that the effect of amlodipine was more marked when calcium channel currents were evoked frequently. Increasing the frequency of activation of calcium channel currents did not alter the apparent onset rate of amlodipine-induced inhibition, but increased the degree of inhibition achieved by the drug. 6. The electrophysiological properties of amlodipine, particularly its voltage-dependence are probably important determinants of its action in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8388295&dopt=Abstract amlodipine Norvasc