amlodipine Norvasc
One-year antihypertensive treatment with amlodipine: effects on 24-hour blood pressure and left ventricular anatomy and function.

Bignotti M, Grandi AM, Gaudio G, Guasti L, Venco A.

Department of Internal Medicine and Medical Therapy, University of Pavia, Ospedale di Circolo, Varese, Italy.

Using digitized M-mode echocardiograms and 24-hour noninvasive ambulatory blood pressure monitoring, we evaluated the effects of 1 year treatment with amlodipine on left ventricular morphology and function in 10 hypertensives with left ventricular hypertrophy. Echocardiograms and 24-hour blood pressure monitoring were performed after 3 weeks of wash-out and after 1 year of oral treatment with amlodipine (5 mg once daily). The therapy significantly lowered blood pressure, without changes in heart rate. Left ventricular mass decreased in all the patients and peak lengthening rate of left ventricular diameter, index of diastolic function, increased in all, with normalization in 5 of the 6 with basal diastolic impairment. Peak shortening rate of left ventricular diameter, index of systolic function, was normal in all at the basal evaluation and did not change after therapy. The percentage reduction of left ventricular mass index significantly correlated with percentage decrease of 24-hour and day-time systolic and diastolic blood pressure. Amlodipine is able to induce regression of left ventricular diastolic function and no changes of systolic function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7610736&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine improves hepatic hemodynamic and metabolic function in the isolated perfused rat liver after sequential cold and warm ischemia.

Piratvisuth T, Dunne JB, Williams R, Tredger JM.

Institute of Liver Studies, King's College Hospital, London, United Kingdom.

Amlodipine, a long acting calcium antagonist, was used to reduce the adverse effects of ischemic/reperfusion injury studied in isolated perfused rat livers. Amlodipine (10 mumol/L) was added to University of Wisconsin (UW) solution in which the liver was stored for 24 hr at 4 degrees C and incorporated in the saline flush used to displace the UW solution before 20 min of warm ischemia (at 37 degrees C) and reperfusion. Initial median blood flow at 15 min was significantly higher after amlodipine treatment (2.78 vs. 1.41 ml/min/g of liver without amlodipine treatment, P = 0.013) as was the area under the curve of blood flow for the entire 3-hr perfusion (472 vs. 316 ml/g of liver, P = 0.003). Amlodipine treatment induced corresponding increases in oxygen delivery (1302 vs. 896 mumol of O2/g of liver over 3 hr of perfusion, P = 0.003) and oxygen consumption (279 vs. 242 mumol of O2/g of liver over 3 hr, P = 0.06). Initial bile flow at 15 min was increased 4-fold by amlodipine treatment (17.27 vs. 4.59 mg/hr/g of liver for sequential cold and warm ischemia, P = 0.013), and the median area under the curve of bile flow for the entire perfusion increased to 92.2 vs. 53.9 mg/g of liver (P = 0.0006). Amlodipine treatment also reduced glucose release into the perfusate (116 vs. 149 mmol/L/g of liver min over 3 hr, P = 0.03) and prevented hepatocyte injury by reducing alanine aminotransferase release both initially (0.43 vs. 0.96 IU/L/g of liver, P = 0.055) and overall (343 vs. 797 IU/L/g of liver min, P = 0.048). When amlodipine was added only to the UW solution, blood flow increased by 66% initially (P = 0.02) and 32% overall (P = 0.013), but there was no corresponding improvement in hepatic function. Amlodipine may reduce hepatic ischemic/reperfusion injury by cytoprotective effects on parenchymal and non-parenchymal hepatocytes during both preservation and reperfusion leading to an improvement in liver microcirculation and an inhibition of the release of toxic mediators.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7624939&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Detection and determination of total amlodipine by high-performance thin-layer chromatography: a useful technique for pharmacokinetic studies.

Pandya KK, satia M, Gandhi TP, Modi IA, Modi RI, Chakravarthy BK.

Department of Phytochemistry, Cadila Labs. Ltd., Ahmedabad, India.

A novel analytical method for determination of the total plasma levels (free and protein bound) of the calcium channel blocking agent amlodipine has been developed using a high-performance thin-layer chromatographic (HPTLC) procedure. Detection and quantitation were performed without internal standards. In previously described methods for the estimation of amlodipine by gas chromatography and high-performance liquid chromatography, only the free levels in plasma and serum were quantified at 7% of the total amlodipine level, with the remaining 93% bound to plasma protein and tissue. The present method employs proteolysis of the plasma proteins by incubating plasma for 2 h in pepsin solution. After proteolysis amlodipine is extracted and a known amount of the extract is spotted on precoated silica-gel 60 F254 plates using a Camag Linomat IV autosampler. Amlodipine was quantified using a dual-wavelength TLC scanner. The method provides a direct estimate of the total amlodipine present in plasma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7663705&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Residual inhibition in density of [3H]isradipine binding sites in rat brain membrane pretreated with amlodipine.

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

Department of Pharmacology, Niigata College of Pharmacy, Japan.

AIM: To test changes in the density of [3H] isradipine binding sites in rat brain membrane pretreated with amlodipine and to compare with those of nifedipine and (+) SM-6586 (methyl 1, 4-dihydro-2, 6-dimethyl-3-(3-(N-benzyl-N-methylaminomethyl)-1,2,4- oxadiazolyl-5-yl)-4-(3-nitrophenyl) pyridine-5-carboxylate). METHODS: The membrane-enriched fractions were prepared from rat brain. The brain membranes were preincubated with nifedipine (10 nmol L-1), amlodipine (1 mumol L-1) and SM-6586 (1 nmol L-1) or with no antagonists added for 45 min, and washing and centrifugation were performed 3 times. They were assayed with [3H]isradipine in incubation media. The Kd and Bmax values of the membrane fractions pretreated with the drugs were determined by Scatchard analysis. RESULTS: The blockage of the [3H]isradipine binding sites induced by nifedipine was reversed by washing, enabling the low values of the specific binding sites to be observed. The blockages by amlodipine and SM-6586, on the other hand, were not readily reversed. No significant difference was found, however, between in the Kd walues of these drugs. CONCLUSION: Amlodipine and SM-6586 are Ca2+ antagonists which dissociate slowly from the Ca2+ channel in membranes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7668092&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Cardiovascular effects of benidipine and amlodipine in isolated tissues and anesthetized dogs.

Moriyama T, Karasawa A.

Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.

Benidipine and amlodipine, 1,4-dihydropyridine calcium channel blocking drugs, are long-acting antihypertensive and antianginal drugs. In the present study, the vascular-selectivity and duration of action of benidipine were determined in vitro and in vivo, and compared with those of amlodipine. The relaxing effect of benidipine on the canine coronary artery precontracted by KCl (55 mM) was about 40 times that of amlodipine. The negative inotropic effect of benidipine in the electrically-stimulated canine right ventricular papillary muscle was about twice that of amlodipine. The potency ratios of the vasorelaxing effect in the coronary artery and the negative inotropic effect in papillary muscle were 1300 for benidipine and 67 for amlodipine, respectively. In anesthetized dogs, the maximum hypotensive effect and the duration of action of 3 micrograms/kg (i.v.) benidipine was almost the same as those of 500 micrograms/kg (i.v.) amlodipine. The duration of the hypotensive action of benidipine at 10 micrograms/kg (i.v.) was almost the same as that of amlodipine at 1500 micrograms/kg (i.v.). Amlodipine at 1500 micrograms/kg (i.v.) reduced mean blood pressure and left ventricular dp/dt max immediately after its administration, whereas such transient falls were not observed after the administration of benidipine at 10 micrograms/kg (i.v.). These results suggest that benidipine possesses a stronger vasodilating effect and a higher vascular-selectivity, compared with amlodipine.

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amlodipine Norvasc
Vascular versus myocardial selectivity of dihydropyridine calcium antagonists as studied in vivo and in vitro.

Nordlander M, Abrahamsson T, Akerblom B, Thalen P.

Astra Hassle AB, Preclinical R & D, Molndal, Sweden.

The use of in vitro models for the study of cardiovascular effects of drugs may not be representative for the in vivo therapeutic effects. However, drug effects in vivo are often difficult to assess because of counteracting reflexes and auto-regulatory rearrangements. To solve this dilemma, the present study presents a two-step method using both in vivo and in vitro techniques to investigate vascular versus myocardial selectivity of three dihydropyridine calcium antagonists: amlodipine, felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potency) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivity in vivo was higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from the in vitro studies were: felodipine (1), amlodipine (2) and nifedipine (20). The in vitro results were used to extrapolate the vascular versus cardiac chronotropic selectivity obtained in vivo to a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7753759&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Inhibition of cardiac L-type calcium channels by quaternary amlodipine: implications for pharmacokinetics and access to dihydropyridine binding site.

Kwan YW, Bangalore R, Lakitsh M, Glossmann H, Kass RS.

Department of Physiology, University of Rochester School of Medicine and Dentistry, NY 14642-8642, USA.

We have used whole cell patch clamp procedures to investigate the inhibition of L-type calcium channel currents in guinea pig ventricular cells by the permanently charged dihydropyridine (DHP)compound UK-118,434-05 (quaternary amlodipine, QA). The location of the charge group of this drug molecule is approximately three times closer to the active DHP moiety than is the case for SDZ-207-180, the only other previously-investigated quaternary DHP molecule. Like SDZ-207-180, QA inhibits channel activity only by external application, consistent with an externally, but not internally, accessible binding site, and once blocked, channels do not recover availability by membrane hyperpolarization independent of extracellular pH. However inhibition by QA occurs at roughly 20 x lower potency than comparable inhibition by SDZ-207-180. Low affinity binding to the DHP binding site was confirmed directly with radioligand binding. The permanently charged amlodipine derivative inhibited radioligand DHP binding in partially purified rabbit skeletal muscle transverse tubule membranes with a pseudo-Hill slope close to unity and an IC50 value of 4.2 +/- 0.6 microM. These results indicate that the characteristically slow pharmacokinetics of tertiary amlodipine are due to the unusually stable inhibition of L-channels caused by the ionized fraction of drug molecules. Furthermore, because the distance between the ionized head group and the DHP moiety is so short, the low affinity binding and channel inhibition by QA suggests that the DHP binding site is not on the extracellular domain of the L-channel alpha 1 subunit, but instead must reside within the bilayer or channel pore at a location closer to the extracellular rather than the intracellular face of the membrane.

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amlodipine Norvasc
Time course of action of amlodipine and felodipine in the rat is most rapid in small arteries.

Videbaek LM, Kvist S, Mulvany MJ.

Institute of Pharmacology, University of Aarhus, Denmark.

The time course of action of amlodipine was compared to that of felodipine in rat mesenteric resistance arteries and aorta. Both amlodipine and felodipine caused a concentration-dependent relaxation of K(+)-depolarized resistance arteries: with amlodipine 3 x 10(-8) M and felodipine 10(-9) M, complete relaxation was reached after 40 min and 10 min, respectively. Furthermore, in resistance arteries, the time course of action of both drugs was shortest in vessels with the smallest diameter. In aorta, both drugs caused a marked relaxation of K(+)-induced tone, without reaching a maximal effect within 2 h. Recovery of K(+)-induced tone after both drugs was complete in resistance arteries, but not aorta, within 2 h. In resistance arteries exposed to K+ depolarization or noradrenaline, both drugs displayed the characteristics of 1,4-dihydropyridine Ca2+ channel antagonists. The results show that amlodipine was slower to have an effect than felodipine, but that both drugs acted fastest in the smallest arteries.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7768262&dopt=Abstract amlodipine Norvasc