Biomedical subjects

M F Walter

Publications and source records attributed to M F Walter.

At least 19 recordsLinked to original sources

PubMed2001

The rate of terminal nucleotide loss from a telomere of the mosquito Anopheles gambiae.

Using a single copy pUChsneo transgene insertion at the Anopheles gambiae 2L telomere, this chromosome end was monitored by genomic Southern blots for forty-four mosquito generations. During this time, the chromosome end lost terminal nucleotides at an apparently constant rate of 55 bp/generation, which can be accounted for by incomplete DNA replication and does not imply exonuclease activity. No telomere elongation events were detected, suggesting that a previously described gene conversion event at this transgene does not occur very frequently. Moreover, no evidence for elongation by transposable elements was found, as described in Drosophila melanogaster. These results are consistent with the proposal that gene conversion between complex terminal satellite repeats that are present at natural telomeres, represents the major telomere elongation mechanism in A. gambiae. Such recombination events between repetitive sequences would occur more frequently than between the single copy pUChsneo transgene on the 2L homologues.

Animals↗

PubMed2001

Elevated plasma F2-isoprostanes in patients on long-term hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) patients on long-term hemodialysis (HD) may be under increased oxidative stress, caused by either HD or renal failure. Plasma F2-isoprostanes have been established as an important indicator of in vivo oxidative stress. METHODS: Plasma esterified F2-isoprostanes were measured in 25 HD patients and 23 controls with normal renal function, employing gas chromatography-mass spectrometry with negative chemical ionization (GC-MS-NCI). C-reactive protein (CRP) was determined concurrently in patients and controls by enzyme-linked immunosorbent assay (ELISA). alpha-Tocopherol, retinol, albumin and creatinine were also determined. RESULTS: The average total esterified F2-isoprostanes in the ESRD patients was 1.62 +/- 0.73 vs. 0.27 +/- 0.10 ng/mL in controls (P < 0.001), with no overlap between patients and controls. Plasma F2-isoprostanes in diabetic ESRD patients were similar to F2-isoprostanes in patients with other causes for renal failure. In a subset of 10 of these ESRD patients evaluated eight months after the initial measurement, plasma-esterified F2-isoprostanes were not altered by an individual dialysis session. Average plasma CRP values were also higher in HD patients (P < 0.02), but some patients had CRP values that were similar to controls. In the HD patients, total plasma F2-isoprostanes and plasma CRP were correlated (r = 0.48, P = 0.015). Plasma alpha-tocopherol did not differ between patients and controls, but plasma retinol was higher in patients (3.15 +/- 1.71 micromol/L) than in controls (1.97 +/- 0.51 micromol/L, P < 0.05). CONCLUSIONS: These results are consistent with the hypothesis that oxidative stress in ESRD patients contributes to increased values of esterified plasma F2-isoprostanes, with concurrent increases in plasma CRP levels in some patients. Impaired clearance of esterified F2-isoprostanes may contribute to the elevated levels in renal failure. Plasma esterified F2-isoprostanes may be a useful indicator to evaluate effectiveness of interventions to decrease oxidative stress and associated inflammation.

Aged↗

PubMed2001

Terminal retrotransposons activate a subtelomeric white transgene at the 2L telomere in Drosophila.

Genetically marked P elements inserted into the subtelomeric satellites of Drosophila show repression and variegation of the reporter gene. One such white+ reporter, inserted between the subtelomeric satellite and the terminal HeT-A array in the left arm of chromosome 2 (2L), is sensitive to its context; changes in the structure of the telomere region can be identified by changes in eye color. Addition of HeT-A or TART elements to the 2L terminus increases w+ expression, and loss of sequence from the end decreases expression. This indicates that the telomeric retrotransposons in Drosophila have an activating influence on the repressed subterminal reporter gene. Changes in eye color due to altered expression of the transgene also allow the detection of interactions between homologous telomeres. The 2L arms that terminate in long HeT-A/TART arrays showed increased expression of the subterminal w+ transgene when the terminal repeats on the homologue are absent or markedly shorter. We propose that the chromatin structure of the terminal HeT-A/TART array and the activity of a putative promoter/enhancer element on HeT-A are affected by telomeric interactions. Such trans-activation may reflect control over HeT-A transcription and, thus, transposition activity.

Animals↗

PubMed2000

Streamlined F2-isoprostane analysis in plasma and urine with high-performance liquid chromatography and gas chromatography/mass spectroscopy.

F2-Isoprostanes in plasma and urine are generally determined by labor-intensive methods requiring sample purification by solid-phase extraction and thin-layer chromatography (TLC). A streamlined and more sensitive method for the measurement of esterified plasma F2-isoprostanes was developed by replacing these steps with high-performance liquid chromatography (HPLC) using an amino column with a hexane/2-propanol gradient. Pentafluorobenzyl esters of F2-isoprostanes were prepared and purified by HPLC, silylated, and then analyzed by gas chromatography (GC) with negative chemical ionization mass spectroscopy (NCI-MS). This method permits analysis with lower plasma volumes (100 microL) and greater sensitivity (to 10 pg; allowing detection to 50 pg/mL) than provided by other methods. Urinary F2-isoprostanes can also be efficiently quantified by this method, with 8-iso-PGF2alpha being identified as a major isomer. With this procedure, esterified plasma F2-isoprostanes were found to be 8.3-fold higher in an end-stage renal failure patient on hemodialysis and urinary 8-iso-PGF2alpha was 7.1-fold higher in a cigarette smoker than respective control subjects. This method, particularly the substitution of the TLC step common to other methods with HPLC, results in a more sensitive and reproducible assay.

Chromatography, High Pressure Liquid↗

PubMed2000

A telomeric satellite in Drosophila virilis and its sibling species.

Telomere elongation by telomerase is the most widespread mechanism among eukaryotes. However, alternative mechanisms such as homologous recombination between terminal satellite DNAs are probably used in lower dipteran insects and in some plants. Drosophila melanogaster uses the very unusual telomere elongation pathway of transposition of telomere-specific retrotransposable elements. The uniqueness of this telomere elongation mechanism raises the question of its origin. We, therefore, analyzed sequences located at telomeres of fairly distantly related Drosophila species, and in this paper we describe the characterization of complex satellite DNA sequences located at the telomeres of D. virilis and other species in the virilis group. We suggest an involvement of these DNA satellites in telomere elongation by homologous recombination similar to that found in lower dipterans. Our findings raise the possibility that telomere elongation by specific retrotransposons as found in D. melanogaster and its sibling species is a recent event in the evolution of dipteran insects.

Animals↗

PubMed2000

Control of telomere elongation and telomeric silencing in Drosophila melanogaster.

Chromosome length in Drosophila is maintained by the targeted transposition of two families of non-LTR retrotransposons, HeT-A and TART. Although the rate of transposition to telomeres is sufficient to counterbalance loss from the chromosome ends due to incomplete DNA replication, transposition as a mechanism for elongating chromosome ends raises the possibility of damaged or deleted telomeres, because of its stochastic nature. Recent evidence suggests that HeT-A transposition is controlled at the levels of transcription and reverse transcription. HeT-A transcription is found primarily in mitotically active cells, and transcription of a w+ reporter gene inserted into the 2L telomere increases when the homologous telomere is partially or completely deleted. The terminal HeT-A array may be important as a positive regulator of this activity in cis, and the subterminal satellite appears to be an important negative regulator in cis. A third chromosome modifier has been identified that increases the level of reverse transcriptase activity on a HeT-A RNA template and greatly increases the transposition of HeT-A. Thus, the host appears to play a role in transposition of these elements. Taken together, these results suggest that control of HeT-A transposition is more complex than previously thought.

Animals↗

PubMed2000

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats.

In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8), Tyr(NH(2))(9)]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonist-treated rats GFR was modestly reduced (P<0.05), and there were large falls in both absolute and fractional sodium excretion (P<0.01 in each case) and absolute and fractional water excretion (P<0.05 in each case), indicating effects on both filtered load and fractional tubular reabsorption. The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule. We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.

Animals↗

PubMed1999

Distribution and fluidizing action of soluble and aggregated amyloid beta-peptide in rat synaptic plasma membranes.

The effects of soluble and aggregated amyloid beta-peptide (Abeta) on cortical synaptic plasma membrane (SPM) structure were examined using small angle x-ray diffraction and fluorescence spectroscopy approaches. Electron density profiles generated from the x-ray diffraction data demonstrated that soluble and aggregated Abeta1-40 peptides associated with distinct regions of the SPM. The width of the SPM samples, including surface hydration, was 84 A at 10 degrees C. Following addition of soluble Abeta1-40, there was a broad increase in electron density in the SPM hydrocarbon core +/-0-15 A from the membrane center, and a reduction in hydrocarbon core width by 6 A. By contrast, aggregated Abeta1-40 contributed electron density to the phospholipid headgroup/hydrated surface of the SPM +/-24-37 A from the membrane center, concomitant with an increase in molecular volume in the hydrocarbon core. The SPM interactions observed for Abeta1-40 were reproduced in a brain lipid membrane system. In contrast to Abeta1-40, aggregated Abeta1-42 intercalated into the lipid bilayer hydrocarbon core +/-0-12 A from the membrane center. Fluorescence experiments showed that both soluble and aggregated Abeta1-40 significantly increased SPM bulk and protein annular fluidity. Physico-chemical interactions of Abeta with the neuronal membrane may contribute to mechanisms of neurotoxicity, independent of specific receptor binding.

Amyloid beta-Peptides↗

PubMed1999

Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine.

The effect of the highly lipophilic calcium channel antagonist (CCA) amlodipine on membrane oxyradical damage was examined and compared to that of other CCA analogs and a sulfhydryl-containing ACE inhibitor in isolated membrane vesicles enriched with polyunsaturated fatty acids (PUFA). Under physiological-like conditions, the dihydropyridine CCA amlodipine significantly (P<0.001) inhibited lipid peroxide formation (>10(2) microM) at concentrations as low as 10.0 nM. Under identical conditions, inhibition of lipid peroxide formation was not observed with representative CCA analogs (felodipine, verapamil, diltiazem) or the ACE inhibitor, captopril, at concentrations as high as 1.0 microM. The potent antioxidant activity of amlodipine is attributed to distinct membrane physico-chemical interactions. High-resolution differential scanning calorimetry showed that amlodipine effected marked changes in membrane thermodynamic properties as compared to other CCA analogs, including a marked reduction in the thermal phase transition temperature (-2.6 degrees C), enthalpy (-4.8 J/g) and cooperative unit size (-59%), relative to control samples. These findings indicate that the chemical structure of amlodipine contributes to distinct membrane biophysical interactions that lead to potent lipid antioxidant effects, independent of calcium channel modulation. These findings provide insights into potential new mechanisms of action for the charged CCA amlodipine.

Amlodipine↗

PubMed1999

Antioxidant capacity of oat (Avena sativa L.) extracts. 1. Inhibition of low-density lipoprotein oxidation and oxygen radical absorbance capacity.

Milled oat groat pearlings, trichomes, flour, and bran were extracted with methanol and the fractions tested in vitro for antioxidant capacity against low-density lipoprotein (LDL) oxidation and R-phycoerythrin protein oxidation in the oxygen radical absorbance capacity (ORAC) assay. The oxidative reactions were generated by 2,2'-azobis(2-amidinopropane) HCl (AAPH) or Cu(2+) in the LDL assay and by AAPH or Cu(2+) + H(2)O(2) in the ORAC assay and calibrated against a Trolox standard to calculate Trolox equivalents (1 Trolox equivalent = 1 TE = activity of 1 micromol of Trolox). The antioxidant capacity of the oat fractions was generally consistent with a potency rank of pearlings (2.89-8.58 TE/g) > flour (1.00-3.54 TE/g) > trichome (1.74 TE/g) = bran (1.02-1.62 TE/g) in both LDL and ORAC assays regardless of the free radical generator employed. A portion of the oat antioxidant constituents may be heat labile as the greatest activity was found among non-steam-treated pearlings. The contribution of oat tocols from the fractions accounted for <5% of the measured antioxidant capacity. AAPH-initiated oxidation of LDL was inhibited by the oat fractions in a dose-dependent manner, although complete suppression was not achieved with the highest doses tested. In contrast, Cu(2+)-initiated oxidation of LDL stimulated peroxide formation with low oat concentrations but completely inhibited oxidation with higher doses. Thus, oats possess antioxidant capacity most of which is likely derived from polar phenolic compounds in the aleurone.

Antioxidants↗

PubMed1999

Moose, a new family of LTR-retrotransposons in the mosquito Anopheles gambiae.

A novel LTR retrotransposable element called moose has been cloned and characterized from the malaria transmitting mosquito, Anopheles gambiae. This element has all the characteristic features of LTR retroelements and is related to retroelements from other insects and nematodes, belonging to a subgroup of retroelements distinct from the copia/Ty1 and gypsy/Ty3 groups. The moose element appears to be active in A. gambiae, and strong RNA expression is detected in the male and female gonads. The use of this retroelement as a potential vector for germ line transformation is discussed.

Amino Acid Sequence↗

PubMed1999

Molecular cloning and tissue-specific expression of the mutator2 gene (mu2) in Drosophila melanogaster.

We present here the molecular cloning and characterization of the mutator2 (mu2) gene of Drosophila melanogaster together with further genetic analyses of its mutant phenotype. mu2 functions in oogenesis during meiotic recombination, during repair of radiation damage in mature oocytes, and in proliferating somatic cells, where mu2 mutations cause an increase in somatic recombination. Our data show that mu2 represents a novel component in the processing of double strand breaks (DSBs) in female meiosis. mu2 does not code for a DNA repair enzyme because mu2 mutants are not hypersensitive to DSB-inducing agents. We have mapped and cloned the mu2 gene and rescued the mu2 phenotype by germ-line transformation with genomic DNA fragments containing the mu2 gene. Sequencing its cDNA demonstrates that mu2 encodes a novel 139-kD protein, which is highly basic in the carboxy half and carries three nuclear localization signals and a helix-loop-helix domain. Consistent with the sex-specific mutant phenotype, the gene is expressed in ovaries but not in testes. During oogenesis its RNA is rapidly transported from the nurse cells into the oocyte where it accumulates specifically at the anterior margin. Expression is also prominent in diploid proliferating cells of larval somatic tissues. Our genetic and molecular data are consistent with the model that mu2 encodes a structural component of the oocyte nucleus. The MU2 protein may be involved in controlling chromatin structure and thus may influence the processing of DNA DSBs.

Amino Acid Sequence↗

PubMed1999

Atheroprotection with amlodipine: cells to lesions and the PREVENT trial. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial.

Oxidized lipid and calcium regulatory abnormalities appear to play important roles in early atherogenesis secondary to cholesterol enrichment of the cell membrane in endothelial and arterial smooth muscle cells (SMCs). However, the link between the two is poorly understood. The findings reviewed here demonstrate that amlodipine has membrane-modifying and antioxidant actions at the cell membrane level in addition to its classical calcium channel blocking properties. These multiple pharmacologic actions may explain the cellular mechanisms of the atheroprotective effects of amlodipine in spontaneous atherogenesis and in accelerated atherosclerotic syndromes. Recent animal model studies have demonstrated that amlodipine inhibits the progression of atherosclerotic lesions and protects against restenosis after angioplasty. Amlodipine inhibits the cholesterol-induced increase in calcium permeability in SMCs, and has been shown to repair abnormalities in SMC membrane structure. Recent data have also demonstrated that amlodipine has a marked antioxidant action in membrane bilayers enriched with polyunsaturated fatty acids. However, these findings have been in animal models only; the efficacy of amlodipine in atheroprotection in humans cannot be predicted. The PREVENT trial has therefore been launched to examine the atheroprotective potential of amlodipine in spontaneous lesion development in humans with ischemic heart disease and in the prevention of restenosis after angioplasty.

Amlodipine↗

PubMed1998

Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions.

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension, angina, and congestive heart failure. SB 211475 (4-[2-hydroxyl-3-[[2-(2-methoxyphenoxy)ethyl]amino]propoxyl]-9H-++ +carbazol-3-ol), a hydroxylated carvedilol analogue, is an even more potent antioxidant in several assay systems. Carvedilol also has neuroprotective capacity with modulatory actions at N-methyl-D-aspartate (NMDA) receptors and Na+ channels. In the present study, we demonstrated that in cultured rat cerebellar neurons, SB 211475 has 28-fold greater antioxidant activity than carvedilol, but is 2- to 6-fold less potent, respectively, at inhibiting neurotoxic activities at Na+ channels and at NMDA receptor channels. To determine a biophysical rationale for these differential activities, small angle x-ray scattering data were obtained from model lipid and brain membrane bilayers containing either carvedilol, SB 211475, or dihydropyridine calcium channel blockers. Electron density profiles revealed that the location of SB 211475 was restricted to the glycerol backbone/hydrocarbon interface and significantly reduced membrane width by 5%, whereas the time-averaged location for carvedilol and flunarizine also extended to the hydrated surface of the bilayer. Comparison of carvedilol with several dihydropyridines showed a correlation between high ClogP values (lipophilicity), Na+ channel inhibitory potency, and bilayer localization. The antioxidant activity of SB 211475 could be explained by restricted intercalation into the glycerol phosphate/hydrocarbon interface, creating an increase in volume associated with the phospholipid acyl chains, which would then become resistant to lipid peroxidation. Differential channel modulation may also be explained by these membrane structural results, which indicate that carvedilol and the less spatially restricted dihydropyridine molecules are more likely to inhibit transmembrane receptor channels.

Animals↗

PubMed1998

Antioxidant and cytoprotective activities of the calcium channel blocker mibefradil.

Mibefradil is a new calcium channel antagonist (CCA) that acts on both L- and T-type channels, with 10-fold selectivity for T-type channels. In this study, the structural interactions of mibefradil with cardiac membrane lipid bilayers were directly examined with small-angle x-ray diffraction approaches and correlated with lipid peroxidation and bovine aortic endothelial cell viability assays. Electron density profiles (A vs electrons/A3) calculated from the diffraction data (37 degrees C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 A from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0-11 A from the center of the cardiac membrane concomitant with a 7.5% (3 A) decrease in membrane hydrocarbon core thickness; these changes in membrane structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of membrane physico-chemical interactions, mibefradil inhibited (10-500 nM) lipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability (IC50 of 2 microM) following acute oxy-radical generation by dihydroxyfumarate and Fe-ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical structure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress.

Animals↗

PubMed1998

DNA organization and length polymorphism at the 2L telomeric region of Anopheles gambiae.

The molecular structure of the telomeric region at the left arm of the second chromosome of the mosquito Anopheles gambiae has been determined in the transformed strain G418 that contains a pUChsneo transgene attached at the 2L chromosome end, and in the Pink eye laboratory strain (PE). Both strains contain the same complex satellite positioned distal to a unique region. FIGE mapping of the telomeric region of the PE strain revealed distinct DNA fragment lengths that segregated with individual chromosomes. Genomic DNA fragments were cloned from the 2L telomeric region, which accounted for about half of 2L chromosomes in the PE population. In all three cases studied, long fragments of different middle repetitive sequences were found attached to the distal ends of the 2L satellite. We propose that random fragments of DNA may be occasionally added during recombination between complex satellite repeats at the chromosome ends.

Animals↗

PubMed1998

Influence of pretreatment and experimental conditions on electrophoretic mobility and hydrophobicity of Cryptosporidium parvum oocysts.

Surface properties of Cryptosporidium parvum oocysts were investigated by using electrophoretic mobility and hydrophobicity measurements. Oocysts purified from calf feces by several sucrose flotation steps and deionized water (DI) washes (DIS method) had an electrophoretic mobility (neutral surface charge) near 0.0 m2 V-1 s-1 over a pH range of 2 to 10. The mean electrophoretic mobility of oocysts stored in DI containing a mixture of antibiotics had a lower standard deviation (sigma = 0.36) than that of oocysts stored in DI without antibiotics (sigma = 0.53); their electrophoretic mobility remained unchanged up to 121 days after collection. The electrophoretic mobility of oocysts purified on a cold Percoll-sucrose gradient after the feces was defatted with ethyl acetate (EAPS method) varied linearly with pH from 0.0 m2 V-1 s-1 at pH 2.4 to -3.2 x 10(-8) m2 V-1 s-1 at pH 10 (sigma = 0.52), thus displaying the negative surface charge at neutral pH observed by other researchers. The hydrophobicity of oocysts and two types of polystyrene beads was measured as a function of ionic strength by adhesion to polystyrene. Oocysts were purified by the DIS method. The ionic strength of the suspending solution was varied from 0 to 95 mmol liter-1. Two-week-old oocysts exhibited strong adhesion ( approximately 85%) at ionic strengths of 0 to 10 mmol liter-1 and moderate adhesion ( approximately 20%) at ionic strengths of 20 to 95 mmol liter-1. Two-month-old oocysts exhibited high adhesion ( approximately 60 to 80%) at all ionic strengths. These results show that adhesion properties governed by the electrophoretic mobility of purified C. parvum oocysts can be altered by the method of purification and that hydrophobicity can change as oocysts age.

Animals↗

PubMed1997

Cholesterol, calcium and atherosclerosis: is there a role for calcium channel blockers in atheroprotection?

It is well known that the atherogenic dyslipidemias of either elevated serum LDL or reduced HDL levels correlate with the degree and severity of atherosclerosis. However, how this leads to atherogenesis is poorly understood. A role for cellular oxidative stress mediated by oxidized LDL has gained widespread acceptance, but this pathway is unlikely to be the sole atherogenic signal. Recent evidence obtained from arterial smooth muscle cells (SMC) and endothelial cells (EC) is consistent with another pathway that may explain, in part, the early alterations contributing to the initiation of cellular atherogenic modifications. This pathway involves enrichment of the cell plasma membrane with cholesterol. In SMC, in vitro (cell culture) and in vivo (cholesterol feeding) experiments demonstrate that cholesterol enrichment of the SMC membrane occurs rapidly and is associated with an increase in membrane bilayer width, calcium permeability, and cell proliferation. Removal of excess membrane cholesterol with human HDL restores these alterations, suggesting that this membrane structural 'defect' mediates these changes in cell function. In vitro, the increased calcium permeability is inhibitable by calcium channel blockers (CCBs), but in vivo, a calcium 'leak' pathway develops that is virtually uninhibitable. It is not surprising that the literature on the application of CCBs for atheroprotection is not wholly convincing. However, with the advent of the new third generation of CCBs, new hope arises. One of the first CCBs of this generation is amlodipine (Norvasc), a charged dihydropyridine that has a remarkable pharmacologic profile. First, it is markedly lipophilic allowing it to partition readily into cell membranes. Second, in the membrane it has the ability to re-order, or restore, the 'swollen' membrane bilayer back to normal in atherosclerotic SMC. Third, it has potent antioxidant properties. Fourth, it appears to inhibit the expression of a variety of genes implicated in atherogenesis. Fifth, it is a CCB. Amlodipine has demonstrated atheroprotection in both rabbit and subhuman primate models of this disease. We propose that cellular alterations induced by enrichment of the cell membrane with cholesterol, which appears to modulate SMC to the atherosclerotic phenotype, are inhibitable by amlodipine through a combination of its varied pharmacologic properties. The potential for atheroprotection with amlodipine is currently being investigated in a human trial (PREVENT trial) and the results of this trial will determine the relevance of the preclinical findings to humans.

Amlodipine↗