amlodipine Norvasc
In-vitro negative chronotropic and inotropic effects of a novel dihydropyridine derivative, CD-832, in the guinea-pig: comparison with calcium-channel antagonists.

Noguchi K, Takahashi K, Higuchi S.

Pharmacology Laboratory, Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co. Ltd, Saitama, Japan.

The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro -2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate) , a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca2+-channel antagonists. All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 > nicardipine = gallopamil > clentiazem > nifedipine = efonidipine > amlodipine = semotiadil > verapamil > diltiazem; that for the negative inotropic effect was nicardipine = gallopamil > nifedipine > verapamil > CD-832 > diltiazem > clentiazem > efonidipine = semotiadil > amlodipine. The ratio of the EC50 (the concentration of Ca2+ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca2+ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11.4, 0.29, 0.87, 35.4, 37.1, 0.65, 0.87, 0.92, 7.11 and 30.0, respectively. These findings indicate that CD-832 and the newly developed Ca2+ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This 'chrono-selective' effect of these drugs might be of benefit in the treatment of cardiovascular disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9600727&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Cardioprotective effects of an angiotensin-converting-enzyme inhibitor, imidapril, and Ca2+ channel antagonist, amlodipine, in spontaneously hypertensive rats at established stage of hypertension.

Yokota S, Naito Y, Yoshida H, Ohara N, Adachi T, Narita H.

Laboratory of Applied Pharmacology, Hatano Research Institute, Food and Drugs Safety Center, Hadano, Kanagawa, Japan.

The present study was performed to compare cardioprotective effects of an angiotensin-converting-enzyme inhibitor, imidapril, and of a Ca2+ channel antagonist, amlodipine, against the cardiac hypertrophy in male spontaneously hypertensive rats (SHRs) at the established stage of hypertension. Fifteen-week-old SHRs were given imidapril (2 and 5 mg/kg/day) or amlodipine (10 mg/kg/day) by gavage for 8 weeks. Three hours after the 1st treatment, imidapril moderately reduced blood pressure without changing heart rate, while amlodipine caused a marked reduction in blood pressure accompanied by transient tachycardia. At the end of the treatments, ventricular weight in the imidapril-treated groups was markedly lower, but that in the amlodipine-treated group was only slightly lower than that in the vehicle-treated group. Myocardial collagen content in the imidapril-treated group tended to be decreased, and significant reduction was observed in the low-dose group. In another experiment, the isolated heart of the imidapril-treated animals demonstrated better cardiac compliance than that in the vehicle-treated animals. In contrast, amlodipine failed to improve cardiac function. The present results suggest that imidapril possesses advantageous effects to prevent cardiac hypertrophy and deteriorated cardiac function in SHRs of established stage of hypertension as compared with amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9639063&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine dynamic effects and myocardial pharmacokinetics in the isolated and perfused guinea-pig heart.

Jeppesen P, Bruun J, Nielsen-Kudsk F.

Institute of Pharmacology, University of Aarhus, Denmark.

Myocardial dynamic effects and pharmacokinetics of amlodipine were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min. Whereas disposition exhibited two-compartment characteristics with phasic half-lives of 25 and 174 min., respectively. Myocardial drug accumulation was increased by 600 times at steady-state compared to the perfusion liquid. Dynamic effect parameters were studied during increasing amlodipine concentrations from 0.16 to 220 nM. Dynamic steady-states developed within 20 min. Coronary flow-rate increased with an Emax of 119% and an EC50 of 1.2 x 10(-8) M. Amlodipine produced inhibitory effects on contraction amplitude and velocities of contraction and relaxation. Observed Emax-values and curve-fitted EC50-values were: 97, 97 and 94% and 1.10(-8), 7.7 x 10(-9) and 2.1 x 10(-8) M, respectively. Heart frequency was not changed. Oxygen consumption increased markedly to a maximum of 44% at 3 x 10(-8) M amlodipine and then decreased to nearly initial values. The frequency-corrected QT-interval decreased to a maximal extent of 20% at the three highest concentrations. Myocardial efficiency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of initial values. The PQ-interval was not changed and the QRS-interval showed only a small but significant decrease at the highest amlodipine concentration. No arrythmogenic effects were observed. The study demonstrated a very slow accumulation and disposition of amlodipine in the guinea-pig heart with a steady-state myocardial drug concentrating accumulation of 600 times. Marked increase in coronary flow-rate and oxygen consumption accompanied by a progressive negative inotropic effect were observed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9646331&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats.

Wagner C, Kramer BK, Hinder M, Kieninger M, Kurtz A.

Physiologisches Institut, Universitat Regensburg, Germany.

1. This study aimed to investigate and to compare the effects of pharmacological T-type calcium channel and of L-type calcium channel blockade on the renin system. To this end, male healthy Sprague-Dawley rats were treated with the T-channel blocker mibefradil or with the L-channel blocker amlodipine at doses of 5 mg kg(-1), 15 mg kg(-1) and 45 mg kg(-1) per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined. 2. Whilst amlodipine lowered basal systolic blood pressure at 5 mg kg(-1), mibefradil had no effect on basal blood pressure in the whole dose range examined. Amlodipine dose-dependently induced up to 7 fold elevation of PRA and renin mRNA levels. Mibefradil significantly lowered PRA and renin mRNA levels at 5 mg kg(-1) and moderately increased both parameters at a dose of 45 mg kg(-1), when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerular cells neither amlodipine nor mibefradil (0.1-10 microM) changed renin secretion. 3. In rats unilateral renal artery clips (2K-1C) mibefradil and amlodipine at doses of 15 mg kg(-1) day(-1) were equally effective in lowering blood pressure. In contrast mibefradil (5 mg kg(-1) and 15 mg kg(-1) day(-1)) significantly attenuated the rise of PRA and renin mRNA levels, whilst amlodipine (15 mg kg(-1)) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery clipping. 4. These findings suggest that T-type calcium channel blockers can inhibit renin secretion and renin gene expression in vivo, whilst L-type calcium channel blockers act as stimulators of the renin system. Since the inhibitory effect of T-type antagonists is apparent in vivo but not in vitro, one may infer that the effect on the renin system is indirect rather than directly mediated at the level of renal juxtaglomerular cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9647484&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis.

Akuzawa N, Nakamura T, Kurashina T, Saito Y, Hoshino J, Sakamoto H, Sumino H, Ono Z, Nagai R.

Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.

We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9657629&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Long acting calcium antagonist amlodipine prevents left ventricular remodeling after myocardial infarction in rats.

Shimada T, Yoshiyama M, Takeuchi K, Omura T, Takemoto Y, Kim S, Iwao H, Yoshikawa J.

First Department of Internal Medicine, Osaka City University Medical School, Japan.

OBJECTIVE: The purpose of this study was to examine the effect of amlodipine, a long-acting calcium antagonist, on the left ventricular remodeling, including systolic and diastolic dysfunction, the change of cardiac gene expression in the myocardial infarcted rats (MI). METHODS: On the first day after myocardial infarction, the animals were randomly assigned to amlodipine treatment (n = 8) or untreated groups (MI; n = 9). We then performed Doppler-echocardiographic examinations and measured the hemodynamics at four weeks after myocardial infarction. Following these measurements, their cardiac mRNA was analyzed. RESULTS: Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 22 +/- 1 mmHg and 5 +/- 1 mmHg. Amlodipine reduced LVEDP and CVP to 15 +/- 1 mmHg (P < 0.01) and 3 +/- 0 mmHg (P < 0.01). The weight of right ventricle in MI was significantly larger than in the control rats (Control; 0.48 +/- 0.01 g/kg, MI; 0.79 +/- 0.04 g/kg, P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 +/- 0.3 mm (P < 0.01) (Control; 6.2 +/- 0.3 mm). Amlodipine prevented an increase of the weight of right ventricle (0.62 +/- 0.03 g/kg, P < 0.01) and LVDd (7.9 +/- 0.2 mm, P < 0.01 to MI). The rats in MI showed systolic dysfunction shown by the decreased fractional shortening (Control; 31 +/- 2% versus MI; 15 +/- 1%, P < 0.01), and diastolic dysfunction shown by E wave deceleration rate (Control; 18.1 +/- 2.0 m/s2, MI; 32.6 +/- 2.1 m/s2, P < 0.01). Amlodipine significantly prevented systolic and diastolic dysfunction. The increases in beta-MHC, alpha-skeletal actin, and ANP mRNAs in the non-infarcted left ventricle and right ventricle at four weeks after the myocardial infarction were all significantly suppressed by the treatment with amlodipine. On the other hand, depressed alpha-MHC was restored to normal levels by amlodipine in both regions. CONCLUSIONS: Amlodipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9659445&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Reduction in infarct size by chronic amlodipine treatment in cholesterol-fed rabbits.

Hoshida S, Yamashita N, Kuzuya T, Hori M.

First Department of Medicine, Osaka University School of Medicine, Suita, Japan.

Calcium (Ca)-dependent factors, including cholesterol-induced changes in membrane Ca permeability and Ca deposition into lesions, may contribute to plaque formation and stability during the early and late stages of atherogenesis. Amlodipine can reduce atheroma formation in cholesterol-fed rabbits and may be cardioprotective. We therefore examined the effects of chronic amlodipine treatment (5 mg/kg daily for 10 weeks, p.o.) on infarct size after 30-min coronary occlusion/48-h reperfusion in rabbits fed a diet with or without 1% cholesterol. Infarct size was significantly larger in cholesterol-fed rabbits (72.0 +/- 3.5%, n = 9, mean +/- S.E.M.) than in normal-fed rabbits (47.1 +/- 4.9%, n = 9, P < 0.05). Amlodipine treatment effectively reversed the infarct size augmentation in cholesterol-fed rabbits (46.3 +/- 6.3%, n = 9, P < 0.05), but did not affect infarct size in normal-fed rabbits (51.0 +/- 4.7%, n = 8). In both cholesterol-fed and normal-fed rabbits, Ca content and leukocyte accumulation as assessed by myeloperoxidase activity were significantly higher in the ischemic myocardium than in the nonischemic myocardium. However, Ca content and leukocyte accumulation were markedly elevated in the ischemic myocardium of cholesterol-fed rabbits compared with normal-fed rabbits. Amlodipine treatment effectively reversed this elevation. Acetylcholine showed a marked reduction in endothelium-dependent relaxation in the aorta of cholesterol-fed rabbits, which also was reversed by amlodipine treatment. These results indicate that chronic amlodipine treatment reduces infarct size only in cholesterol-fed rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9678782&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of chronic treatment with amlodipine in non-insulin-dependent diabetic rats.

Gokhale MS, Shah DH, Hakim Z, Santani DD, Goyal RK.

Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, India.

We have investigated the effects of amlodipine on streptozotocin-(STZ) induced neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by intraperitoneal injection of STZ (70 mg kg-1) to 5-day-old rat pups. The animals were weaned at 30 days and maintained with food and water ad libitum for 3 months. Amlodipine (5 mg kg-1 p.o.) was administered for 6 weeks after the animals were confirmed diabetic (3 months after the STZ injection). A group of control animals were also maintained and this group received citrate buffer 5 days after birth. Fasting- and fed-glucose levels in NIDDM rats were significantly higher than control rats. Treatment with amlodipine reduced the elevated fasting- and fed-glucose levels significantly. Results of the oral glucose tolerance test (OGTT) revealed the glucose tolerance is impaired in the NIDDM rats. There was a marked increase in glucose levels after oral administration of glucose in the control NIDDM rats. Increased glucose levels were found to be associated with increased insulin levels. Treatment with amlodipine in the NIDDM rats caused a decrease in insulin release, however, glucose levels were found to be lowered significantly indicating that amlodipine causes an increase in insulin sensitivity. In conclusion, our data indicated that amlodipine increases insulin sensitivity in neonatal-STZ NIDDM rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9695118&dopt=Abstract amlodipine Norvasc