amlodipine Norvasc
Effect of amlodipine on myocardial functional and metabolic recovery following coronary occlusion and reperfusion in dogs.

Gross GJ, Farber NE, Pieper GM.

Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee 53226.

The effects of the dihydropyridine calcium-channel blocker, amlodipine, on subendocardial segment shortening (%SS), regional myocardial blood flow, myocardial high-energy phosphate levels and tissue water content were compared to those of a saline-treated group of barbital-anesthetized dogs subjected to a 45-minute coronary artery occlusion followed by 60 minutes of reperfusion. Saline or amlodipine (200 micrograms/kg, IV) were administered 15 minutes prior to coronary occlusion. There were no significant differences between groups in ischemic bed size or hemodynamics, although dP/dt was higher following amlodipine. Subepicardial collateral blood flow was higher in the amlodipine group during coronary occlusion. Following occlusion, %SS in the ischemic region was markedly decreased in both series and passive systolic lengthening resulted. In spite of similar decreases in %SS during occlusion, the amlodipine- treated dogs showed a marked improvement in myocardial segment function (%SS) of the ischemic-reperfused region throughout 60 minutes of reperfusion as compared to saline-treated animals. In addition, amlodipine prevented the rebound increase in phosphocreatine and attenuated the loss of adenine nucleotides and the increase in tissue water in the ischemic-reperfused area at 60 minutes of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the ischemic-reperfused myocardium, and may have potential as a therapeutic agent for the treatment of coronary artery disease. The mechanism of action of amlodipine in this model is unknown but may be partially related to a drug-induced increase in coronary collateral blood flow.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2535101&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlodipine with uncharged drugs of this class in cardiac membranes.

Mason RP, Campbell SF, Wang SD, Herbette LG.

Department of Radiology, University of Connecticut Health Center, Farmington 06032.

The distinctive pharmacokinetic and pharmacodynamic activity of amlodipine, including long onset and duration of activity as a calcium channel antagonist, may be related to its interactions with membranes. We have used X-ray crystallography and small-angle X-ray scattering to examine and compare the crystal structure of amlodipine and its location in cardiac sarcolemmal lipid bilayers with that of uncharged dihydropyridines (DHPs) such as nimodipine. Crystallographic analysis demonstrated that the DHP ring of amlodipine is considerably more planar than that of nimodipine, that amlodipine has a greater torsion angle between the DHP and aryl rings, and that the protonated amino group extends away from the DHP ring structure. Despite the positive charge of amlodipine at physiological pH, membrane electron density profile structures showed amlodipine to have a time-averaged location near the hydrocarbon core/water interface similar to that observed for several uncharged DHPs. However, unlike uncharged DHPs, this location is consistent with an ionic interaction between the protonated amino function of amlodipine and the negatively charged phospholipid headgroup region, in addition to a hydrophobic interaction with the fatty acyl chain region near the glycerol backbone similar to other DHPs. This location may also provide an appropriate conformation and orientation for amlodipine binding to its receptor site at this depth in the membrane. Finally, we have measured the nonspecific partitioning of amlodipine into native sarcoplasmic reticulum membranes from rabbit skeletal muscle and compared these data with those for the uncharged DHPs. The partition coefficient into light sarcoplasmic reticulum for amlodipine was higher than that observed for most uncharged DHPs and rates of incorporation of amlodipine into membranes were very high, as with other DHPs, whereas the "washout time" of amlodipine from these membranes was longer by over 1 order of magnitude. These data suggest differences in membrane interactions for amlodipine, compared with uncharged DHPs, that may be correlated with its novel pharmacodynamic and pharmacokinetic profile.

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amlodipine Norvasc
Cellular electrophysiology of amlodipine: probing the cardiac L-type calcium channel.

Kass RS, Arena JP, Chin S.

Department of Physiology, University of Rochester Medical Center, New York 14642.

The electrophysiologic properties of amlodipine in single guinea-pig ventricular cells were investigated. The degree of ionization of the drug molecule was found to affect both the development of and the recovery from block of L-type calcium channels. Under alkaline conditions, when most of the drug is in a neutral form, the actions of amlodipine resemble previously described neutral dihydropyridine (DHP) compounds. Under these conditions, calcium channel block by amlodipine is reversibly regulated by cell membrane potential, i.e., block is more pronounced at voltages positive to -50 mV and completely relieved at voltages negative to -80 mV. When the drug molecule is ionized, block develops very slowly at positive membrane potentials and is very difficult to relieve on returning the membrane potential to more negative voltages. It is concluded that the degree of ionization of the drug molecule limits access to the DHP receptor and that the drug-bound receptor can be titrated by extracellular hydrogen ions. These results place limitations on the location of the DHP receptor within the cardiac sarcolemmal membrane.

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amlodipine Norvasc
The hemodynamic properties of amlodipine in anesthetised and conscious dogs: comparison with nitrendipine and influence of beta-adrenergic blockade.

Dodd MG, Gardiner DG, Carter AJ, Sutton MR, Burges RA.

Discovery Biology Department, Pfizer Central Research, Sandwich, Kent, England.

The hemodynamic actions of the new dihydropyridine calcium-channel blocker amlodipine were assessed and compared with those of nitrendipine using anesthetised dogs and were also investigated in conscious dogs with and without beta-adrenergic blockade. After bolus intravenous administration, amlodipine (25 to 1600 micrograms/kg) or nitrendipine (1 to 128 micrograms/kg) was administered to anesthetised dogs at 30-minute intervals, caused dose-related reductions in systemic and coronary vascular resistances with corresponding increases in cardiac output and coronary flow. Nitrendipine, unlike amlodipine, caused marked acute hypotension. The onset of action of amlodipine was markedly slower than that of nitrendipine, and effects were maintained for 30 minutes--recovery from nitrendipine was largely complete at 30 minutes. In conscious dogs, amlodipine (250, 500, 1000 micrograms/kg IV) caused dose-related reductions in systemic vascular resistance that approached maximum within 5 minutes and persisted for over 4 hours. Reflex increases in heart rate, cardiac output, and cardiac contractility were attenuated by prior treatment with propranolol, resulting in earlier and greater falls in blood pressure, but no marked adverse effects on cardiac contraction or conduction. In the absence of propranolol, maximum falls in blood pressure occurred 3 to 4 hours after the dose, possibly as a result of the changed baroceptor sensitivity induced by amlodipine. These results show amlodipine to have the basic hemodynamic profile of other dihydropyridine calcium-channel blockers, but in addition it demonstrates a slower onset and longer duration of action; the reasons behind these pharmacodynamic properties are discussed.

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amlodipine Norvasc
Effects of calcium channel antagonists on action potential conduction and transmitter release in the guinea-pig vas deferens.

Beattie DT, Cunnane TC, Muir TC.

The effects of the Ca2+ channel antagonists amlodipine, cobalt, diltiazem, nifedipine and verapamil and the local anaesthetic lignocaine were investigated on action potential conduction in and on evoked transmitter release from sympathetic nerves in the guinea-pig isolated vas deferens. Transmitter release was investigated by measurement of evoked (trains of pulses at 1 and 2 Hz, 0.1-0.5 ms supramaximal voltage) excitatory junction potentials (e.j.ps) using microelectrodes; tension was recorded simultaneously; tritium [3H] overflow from vasa preincubated (37 degrees C, 30 min) in Krebs solution containing either [3H]-noradrenaline (NA, 25 microCi ml-1, 2 X 10(-6) M NA) or [3H]-adenosine (50 microCi ml-1, 1 X 10(-6) M adenosine). Amlodipine (0.5-2 X 10(-4) M), verapamil (0.5-2 X 10(-4) M), diltiazem (1-8 X 10(-4) M), lignocaine (0.1-2 X 10(-3) M) and cobalt (2-6 X 10(-2) M) in descending order of potency, but not nifedipine (1-5 X 10(-3) M), increased the latency and inhibited, then abolished, the amplitude and number of action potentials in a concentration-dependent manner. Amlodipine (0.5-1 X 10(-4) M), verapamil (1-2 X 10(-4) M), diltiazem (1-5 X 10(-4) M) and cobalt (1 X 10(-3) M), in descending order of potency, but not nifedipine (5 X 10(-4) M), inhibited then abolished evoked e.j.ps in a concentration-dependent manner. Cobalt inhibited e.j.ps at a lower concentration than that (2-6 X 10(-2) M) required to block action potential conduction. In unstimulated tissues, the resting [3H] overflow following preincubation with [3H]-NA consisted largely of 4-hydroxy 3-methoxymandelic acid (VMA), 4-hydroxy 3-methoxy phenylglycol (MOPEG), 3,4 dihydroxyphenylglycol (DOPEG) and NA; stimulated tissues (300 pulses at 20 Hz, 0.5 ms supramaximal voltage) released mainly NA. Verapamil (0.1-1 X 10(-4) M), amlodipine (0.05-1 X 10(-4) M) and nifedipine (1-5 X 10(-4) M), but not cobalt (2 X 10(-3) M), increased, significantly, the resting overflow of 3H comprising mainly DOPEG. Cobalt (2 X 10(-3) M) inhibited, significantly, the stimulation-evoked overflow of 3H. Verapamil (1 X 10(-4) M) had little effect on the resting overflow of 3H following preincubation with [3H]-adenosine. Diltiazem (5 X 10(-4) M) and cobalt (2 X 10(-3) M) both inhibited evoked 3H overflow. Nifedipine (5 X 10(-4) M) was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)

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amlodipine Norvasc
Amlodipine therapy corrects renal abnormalities encountered in the hypertensive state.

Reams GP, Lau A, Hamory A, Bauer JH.

Department of Medicine, University of Missouri School of Medicine, Columbia.

Calcium antagonists may increase glomerular filtration rate and renal plasma flow by antagonizing the intrarenal effects of angiotensin II and/or norepinephrine. We prospectively studied the effects of amlodipine, a once-a-day dihydropyridine calcium channel antagonist, in 19 patients with essential hypertension. Studies were performed after 4 weeks of placebo and 6 weeks of amlodipine therapy, and included the assessment of systolic and diastolic BP, renal clearances of inulin and p-aminohippurate, and determination of body fluid composition. Systolic and diastolic BPs were reduced following 6 weeks of amlodipine monotherapy. In spite of significant decreases in mean arterial pressure, there were increases in inulin clearance (+ 13%), and p-aminohippurate clearance (+ 19%). Filtration fraction was not changed. Renal vascular resistance was decreased (-25%). Total blood volume, extracellular fluid volume, and total body water and body weight were not changed. We conclude that amlodipine therapy has the potential to reverse renal abnormalities encountered in the hypertensive state.

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amlodipine Norvasc
A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats.

Johns EJ.

Department of Physiology, Medical School, Birmingham.

1. An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and anti-natriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone. 2. Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion. 3. In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively. 4. Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
Metabolism and kinetics of amlodipine in man.

Beresford AP, McGibney D, Humphrey MJ, Macrae PV, Stopher DA.

Pfizer Central Research, Sandwich, Kent, UK.

1. The disposition of amlodipine, R,S,2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl- 5- methoxycarbonyl-6-methyl-1,4-dihydropyridine has been studied in two human volunteers using single oral and intravenous doses of 14C-amlodipine. The drug was well absorbed by the oral route while the mean oral bioavailability for unchanged drug was 62.5%. 2. Renal elimination was the major route of excretion with about 60% of the dosed radioactivity recovered in urine. Mean total recovered radioactivity in urine and faeces amounted to 84% for both the oral and intravenous routes. 3. Apart from a small amount of unchanged amlodipine (10% of urine 14C), only pyridine metabolites of amlodipine were excreted in urine. The majority (greater than 95%) of the metabolites excreted in the 0-72 h post-dose period were identified; the major metabolite was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- 2-pyridyl]methoxy) acetic acid and this represented 33% of urinary radioactivity. The data indicate that oxidation of amlodipine to its pyridine analogue is the principal route of metabolism with subsequent metabolism by oxidative deamination, de-esterification and aliphatic hydroxylation. 4. For the two volunteers, amlodipine concentrations in plasma declined with a mean half-life of 33 h, while slower elimination of total drug-related material from plasma was observed, consistent with prolonged excretion (up to 12 days) of metabolites in urine and faeces. Only amlodipine and pyridine metabolites were found in the circulation. As these pyridine derivatives have minimal calcium antagonist activity the efficacy of amlodipine in man can most probably be attributed to the parent drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2967593&dopt=Abstract amlodipine Norvasc