Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria

Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS)-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 μM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity.     

ELECTRICAL REMODELLING OF CHRONIC ATRIAL FIBRILLATION

1. It is now recognized that atrial fibrillation (AF) is not a benign condition, as it is associated with a 40% increase in mortality and a doubling of the risk of stroke. 2. The development of AF leads to mechanical, electrophysiological and cellular changes in the atria that tend to sustain AF. This process is known as atrial remodelling. 3. The three electrophysiological elements in the atria that initiate and sustain AF are: (i) shortening of the refractory period and an increase in dispersion; (ii) slowing of conduction velocity; and (iii) the presence of triggerin. foci. 4. As AF is a heterogeneous disorder, therapeutic strategies include the use of devices (pacemakers and atrial defibrillators), radiofrequency ablation (focal ablation or the creation of linear lines) and drug therapy that may reverse a remodelle. atrium.     

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β^?/? (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β^?/? genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β^?/? mice. Moreover, Pgc‐1β^?/? mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β^?/? mice had shorter repolarisation intervals. These were likely attributable to altered K⁺ conductance properties, ultimately resulting in a shortened QT_c interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β^?/? systems in widespread cardiac regions.     

Effects of 3‐methyladenine on isolated left atria subjected to simulated ischaemia–reperfusion

Although autophagy is a prominent feature of myocardial ischaemia and reperfusion, its functional significance is unclear and controversial. In order to gain a deeper insight into the role of autophagy in myocardial ischaemia‐reperfusion, we explored the effects of the pharmacological inhibitor of autophagy 3‐methyladenine (3‐MA). Isolated rat atria subjected to simulated 75‐min ischaemia/75‐min reperfusion (Is‐Rs) in the presence or absence of 3‐MA were used. The LC3‐II/LC3‐I ratio, an indicator of autophagosome formation, did not increase after ischaemia either in the presence or absence of 3‐MA, but there was significant enhancement during reperfusion, which was prevented by the presence of 3‐MA. The autophagy inhibitor also increased p62 protein, one of the specific substrates degraded through the autophagy‐lysosomal pathway. Electron micrographs showed double membrane autophagosome‐like structures during reperfusion, which were absent in atria subjected to Is‐Rs in the presence of 3‐MA. These findings suggest that this agent inhibited the autophagic flux under the present experimental conditions. Inhibition of autophagy during Is‐Rs was accompanied by a high incidence of tachyarrhythmias during reperfusion, and a decrease in the maximal inotropic response to β‐adrenergic and to calcium stimulation at the end of Is‐Rs. Deterioration of mitochondrial morphology and function, without affecting cell viability, was observed in atria subjected to Is‐Rs in the presence of 3‐MA. The present results suggest an association between the inhibition of autophagy and functional alterations of the cells that have undergone sublethal stress, and have been able to recover in this experimental model of ischaemia–reperfusion.     

Design,synthesis, and negative inotropic evaluation of 4‐phenyl‐1H‐1,2,4‐triazol‐5(4H)‐one derivatives containing triazole or piperazine moieties

In this study, four novel series of 4‐phenyl‐1H ‐1,2,4‐triazol‐5(4H )‐one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of ?48.22 ± 0.36% at a concentration of 3 × 10^?5 mol/L (metoprolol: ?9.74 ± 0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO 2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP ‐sensitive K⁺ channel and L‐type Ca²⁺ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.     

Hippocampal slice cultures integrated with multi‐electrode arrays: a model for study of long‐term drug effects on synaptic activity

Technological limitations have restricted the ability to determine chronic drug effects on synaptic function from in vitro preparations. In earlier studies, the extracellular recording duration was limited to less than 10 h and only a distinct population of neurons was examined. To address these limitations, we used organotypic hippocampal slice cultures integrated with planar multi‐electrode arrays (MEA‐OHSC), which permitted within‐slice comparisons and examination of long‐term changes across multiple populations of neurons. Long‐term potentiation (LTP) is a widely accepted measure of synaptic plasticity, and is believed to be a cellular mechanism underlying learning and memory. Amyloid‐β protein (Aβ) is a 40–42 amino acid peptide that is the primary element of senile plaques, a pathological hallmark of Alzheimer's disease (AD). In contrast to earlier studies, MEA‐OHSCs allowed for long‐term administration of Aβ_1–42 to more closely model the chronic nature of AD pathogenesis. Prior to Aβ_1–42 exposure, the CA1 region displayed robust potentiation, but afterwards the ability to induce LTP was nearly absent. Spatial analysis illustrated, for the first time, the substantial area of LTP induction, and clearly showed the global loss of this plasticity after long‐term Aβ exposure. The MEA‐OHSC model characterized here presents an ideal platform for examining the effects chronic exposure of a bioactive compound can have on a cellular correlate of memory. This model could also be used to screen potential therapeutics that may influence synaptic activity. Drug Dev Res 68:84–93, 2007. Published 2007 Wiley‐Liss, Inc.; Canadian Crown Copyright     

High‐density lipoprotein: A potent inhibitor of inflammation

1. Inflammation is an important process, driving the progression of atherosclerosis. Stemming inflammation may be a mechanism to inhibit the progression of this disease. 2. High‐density lipoprotein (HDL), a particle inversely related to cardiovascular disease, has been described as having a number of anti‐inflammatory functions. It has been shown that HDL inhibits endothelial inflammation in both in vitro and in vivo models, reducing the expression of key cell adhesion molecules. In addition, HDL has been shown to have an effect on the coagulation pathway by inhibiting platelet activation and reducing thrombus formation. Furthermore, by reducing the activation of leucocytes, HDL can inhibit leucocyte recruitment to the endothelium. 3. High‐density lipoprotein infusion studies conducted in patients with inflammatory diseases have shown that acute treatment with HDL can effectively inhibit inflammation in vivo. Thus, HDL has been proven to be a potent inhibitor of inflammation, acting on a number of pathways, and this may suggest that HDL could be applied as an anti‐inflammatory molecule for a number of diseases. 4. The present review highlights these important studies and reviews data on the anti‐inflammatory effects of HDL from in vitro and in vivo studies, in both humans and animal models of atherosclerosis and inflammatory‐related diseases.     

A morpholinocatechol compound (UK42620) with clonidine‐ and tyramine‐like actions

1 The actions of a morpholinocatechol (UK42620) were studied in rat isolated atria preparations consisting of spontaneously beating left and right atrial pairs. 2 UK42620 produced positive inotropic and chronotropic responses and, in atria that were incubated with [³H]‐noradrenaline, it also produced a massive increase in the release of radioactivity. 3 These actions of UK42620 were similar to those of tyramine and were blocked by the β‐adrenoceptor antagonist propranolol (0.3 μM ) and by the neuronal uptake blocker desipramine (1 μM ). 4 In the presence of desipramine, UK42620 but not tyramine produced a decrease in the stimulation‐induced efflux of radioactivity that was antagonized by idazoxan. 5 Thus, UK42620 had prejunctional α₂‐adrenoceptor activity like that of clonidine‐ and tyramine‐like activity releasing large amounts of noradrenaline.     

Increased expression of miR‐34a in mouse spleen one day after exposure to N‐ethyl‐N‐nitrosourea

MicroRNAs (miRNAs) are a class of single‐stranded small RNA molecules (~22 nucleotides) that are not translated into proteins and function as regulators of gene expression. Many miRNAs are involved in carcinogenesis. One of them, miR‐34a, is associated with various p53‐initiated biological processes and may act as a tumor suppressor miRNA. Its expression is generally down‐regulated in tumor tissues and up‐regulated in tissues exposed to carcinogens chronically or subchronically. However, the response of this miRNA to acute exposure of a genotoxic carcinogen is little known. In this study, miR‐34a expression was evaluated in spleen tissues of mice treated with a dose of 120 mg kg^?1 body weight N‐ethyl‐N‐nitrosourea (ENU), a potent mutagenic carcinogen. Real‐time PCR analysis showed that the ENU exposure resulted in a 5.5‐fold increase of miR‐34a expression over the control one day after the treatment. The result suggests that miR‐34a expression responds sensitively to genotoxic insults within a short period after exposure of the mutagen, and therefore, this gene has the potential to be used as an indicator for genotoxin exposure.     

Preparation and Evaluation of 99mTc‐labeled anti‐CD11b Antibody Targeting Inflammatory Microenvironment for Colon Cancer Imaging

CD11b, an active constituent of innate immune response highly expressed in myeloid‐derived suppressor cells (MDSCs), can be used as a marker of inflammatory microenvironment, particularly in tumor tissues. In this research, we aimed to fabricate a ^99mTc‐labeled anti‐CD11b antibody as a probe for CD11b⁺ myeloid cells in colon cancer imaging with single‐photon emission computed tomography (SPECT). In situ murine colon tumor model was established in histidine decarboxylase knockout (Hdc^?/?) mice by chemicals induction. ^99mTc‐labeled anti‐CD11b was obtained with labeling yields of over 30% and radiochemical purity of over 95%. Micro‐SPECT/CT scans were performed at 6 h post injection to investigate biodistributions and targeting of the probe. In situ colonic neoplasma as small as 3 mm diameters was clearly identified by imaging; after dissection of the animal, anti‐CD11b immunofluorescence staining was performed to identify infiltration of CD11b+ MDSCs in microenvironment of colonic neoplasms. In addition, the images displayed intense signal from bone marrow and spleen, which indicated the origin and migration of CD11b⁺ MDSCs in vivo, and these results were further proved by flow cytometry analysis. Therefore, ^99mTc‐labeled anti‐CD11b SPECT displayed the potential to facilitate the diagnosis of colon tumor in very early stage via detection of inflammatory microenvironment.     

The effects of adenosine on isolated right atrial preparations from streptozotocin‐diabetic rats

1 The aim of the present study was to investigate the inhibitory effects of adenosine on the contractile force and chronotropic action of isolated right atrial preparations from streptozotocin (STZ)‐diabetic rats. 2 The rats were anaesthetized with diethyl ether and STZ (65 mg kg^?1) was injected intravenously via the tail vein. 3 Adenosine produced concentration‐dependent decreases in the force of contraction and a negative chronotropic action of atria both in control and diabetic groups. The inhibition responses to adenosine were significantly higher in diabetic rat atria than control. 4 Dypiridamole incubation caused a significant potentiation of the inhibitory effect of adenosine on contractile force and chronotropic action of atria in the control group, but not in the diabetic group. In the presence of dipyridamole, the inhibitory effects of adenosine on measured parameters in diabetic rats were not significantly different from those in control rats. 5 These results suggested that atria from 6 weeks STZ‐diabetic rats exhibited a supersensitivity to the negative inotropic and chronotropic effects of adenosine compared with atria from control rats because of an impairment in adenosine uptake mechanism. Altered sensitivity to effects of adenosine might reflect relatively early changes in the course of diabetes.     

Immunohistochemical and functional studies for M3 muscarinic receptors and cyclo‐oxygenase‐2 expressed in the mouse atrium

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Effects of labedipinedilol‐A,third‐generation dihydropyridine‐type calcium blocker,on ouabain‐induced arrhythmia

Labedipinedilol‐A, a novel dihydropyridine‐type calcium antagonist with α/β‐adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol‐A on ouabain‐induced tonotropy and arrhythmias in isolated whole atria, and using patch‐clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol‐A (10 µM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extra‐systole (arrhythmia) induced by ouabain in isolate atria. In the voltage‐clamp study, labedipinedilol‐A (1–100 µM) reduced the peak amplitude of sodium inward current (I_Na) and L‐type calcium current (I_Ca‐L), and shifted the current‐voltage (I‐V) curve upward in a concentration‐dependent manner. In contrast, the addition of labedipinedilol‐A increased transient outward potassium current (I_to) and inward rectifier potassium current (I_K1) significantly. Labedipinedilol‐A (10 µM) also effectively depressed the isoproterenol‐induced increase in the Ca²⁺ current. These results show that labedipinedilol‐A blocks I_Ca‐L and I_Na, and increases I_to and I_K1. These findings indicate that labedipinedilol‐A produces direct cardiac action, probably due to the inhibition of cardiac Na⁺ and Ca²⁺ channels. Our results suggest that labedipinedilol‐A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain‐induced arrhythmia. Drug Dev Res 69:26–33, 2008 © 2008 Wiley‐Liss, Inc.     

Anti‐oxidant properties of high‐density lipoprotein and atherosclerosis

1. High‐density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. 2. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport. The functions of HDL that have recently attracted attention include anti‐inflammatory and anti‐oxidant activities. High anti‐oxidant and anti‐inflammatory activities of HDL are associated with protection from cardiovascular disease. 3. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Conversely, these activities are compromised in many pathological states associated with inflammation. 4. The focus of the present review is on the anti‐oxidant and anti‐inflammatory functions of HDL and its individual components in relation to protection from atherosclerosis.     

射频消融治疗起源于主动脉无冠窦的房性心动过速的效果

目的:探讨起源于主动脉无冠窦或其邻近组织的房性心动过速(房速)的电生理特性及射频消融治疗的效果。方法:选择阵发性房速患者10例,术中予心房或心室刺激诱发房速,分别在右心房、主动脉无冠窦内进行心房激动标测,分析体表心电图P波及窦性心律时P波特点,最后均于无冠窦内进行射频消融治疗。结果:心房刺激均能反复诱发和终止10例患者的房速,右心房的前间隔希氏束上部标测出相对提前的心房激动,但多次射频消融未成功,后于主动脉无冠窦内标测出心房激动较体表心电图提前,放电后终止10例房速的发作。房速时P波间期明显短于窦律时,差异有统计学意义(P<0.05)。术后随访(12.5±5.3)个月,均无房速复发及手术相关并发症出现。结论:经主动脉无冠窦内射频消融可作为治疗消融前间隔希氏束部位失败的一种新方法。     

The response of isolated rabbit atria to aconitine

The arrhythmias observed in isolated rabbit atria appear to be due to two actions of aconitine. One is an apparent direct stimulant effect on the sino-atrial node and the other is a depressant effect on the processes involved in intra-atrial propagation of impulses. Acetylcholine has either an inhibitory or stimulatory effect on atria pretreated with aconitine because it antagonizes the actions of aconitine both on the sinus node and on conduction. When conduction block is not apparent, acetylcholine depresses the atrial rate. On the other hand, when conduction is markedly depressed, acetylcholine increases the atrial rate.     

Determination of sulfur‐containing antibiotics using high‐performance liquid chromatography with integrated pulsed amperometric detection

Sulfur‐containing antibiotics (e.g., ampicillin, penicillin, lincomycin, cephalosporin, and sulfanilamide) are a general class of compounds that have antibacterial properties. Some of these antibiotics lack a strong chromophore, and consequently are poorly detected using absorbance detection. The presence of oxidizable sulfur within an antibiotic’s molecular structure allows its direct detection by pulsed amperometry. Pulsed amperometry is an electrochemical detection method that uses a pulsed potential‐time waveform at a noble metal electrode surface to electrocatalytically oxidize analytes in proportion to concentration. The current for sulfur compounds on a gold (Au) electrode is caused by the desorption of the analyte previously adsorbed at the oxide‐free Au surface. Current integration in conjunction with rapidly changed voltage potentials is termed integrated pulsed amperometric detection (IPAD). Recent publications using high‐performance liquid chromatography (HPLC) with IPAD have demonstrated the capability to measure sulfur antibiotics. Our investigations of HPLC‐IPAD showed poor long‐term peak area reproducibility for these drugs. In this article, we present a new IPAD waveform that we demonstrate has good long‐term (>2 months) peak area reproducibility (4–5% relative s.d.). We show that a broad spectrum of sulfur‐antibiotic chemical structures can be detected, and we compare IPAD to absorbance detection. For nonchromophoric sulfur‐containing antibiotics, IPAD showed greater sensitivity than absorbance detection. The lower limits of detection, linearities, and peak area precision are compared for both IPAD and absorbance detection methods using seven antibiotics representing a diversity of chemical structures, including one nonsulfur‐containing antibiotic. The stabilities of cephradine and cephapirin were monitored using both IPAD and absorbance detections. Cephradine showed high chemical stability in aqueous ambient conditions at 10 μg/ml, whereas cephapirin showed a decomposition rate of 10% per day by both detection techniques. Some decomposition products could only be detected by IPAD. High recoveries were demonstrated for two antibiotics (sulfamethoxazole and trimethoprim) in a pharmaceutical tablet formulation. For the same formulation, the feasibility of conducting a dissolution study was also demonstrated. IPAD is a good primary detection method to complement or replace absorbance detection for nonchromophoric sulfur‐containing antibiotics and their sulfur‐containing impurities and decomposition products. HPLC‐IPAD is also a good confirming technique for sulfur antibiotics with chromophoric properties, and their impurities and decomposition products. Drug Dev. Res. 53:268–280, 2001. © 2001 Wiley‐Liss, Inc.     

The guinea‐pig expresses functional CYP2C and P‐glycoprotein: further validation of its usefulness in drug biotransformation/transport studies

Background: The guinea‐pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of drug‐metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea‐pig also expresses a functional CYP2C drug‐metabolizing enzyme and the P‐glycoprotein (P‐gp) drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P‐gp were obtained from guinea‐pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P‐gp. The functional enzymatic activity of guinea‐pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific drug substrates in HPLC analyses. To further study both P‐gp and CYP2C functional activities, the guinea‐pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein‐acetoxymethyl ester (AM) accumulation assays or 14,15‐EET/DHET formation experiments were performed to evaluate either P‐gp transport activity or CYP2C epoxygenase activity, respectively. The guinea‐pig tissue distribution of P‐gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea‐pig liver microsomal preparations. CYP2C‐mediated biotransformation of diclofenac and tolbutamide were shown. Expression of P‐gp protein was detected in guinea‐pig liver and small intestine. Functional activity of guinea‐pig P‐gp was demonstrated in ABCB1/MDR1‐transfected cells. GP‐CYP2C‐transfected cells also showed functional epoxygenase activity. Conclusion: The guinea‐pig expresses functional CYP2C and P‐gp, thus suggesting its usefulness for further validating data obtained with other animal models in drug biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of gadolinium on stretch-induced changes in contraction and intracellularly recorded action- and afterpotentials of rat isolated atrium.

1. Atrial arrhythmias, like atrial fibrillation and extrasystoles, are common in clinical situations when atrial pressure is increased. Although cardiac mechanoelectrical feedback has been under intensive study for many years, the mechanisms of stretch-induced arrhythmias are not known in detail. This is partly due to methodological difficulties in recording intracellular voltage during stretch stimulation. In this study we investigated the effects of gadolinium (Gd3+), a blocker of stretch-activated (SA) channels, on stretch-induced changes in rat atrial action potentials and contraction force. 2. By intracellular voltage recordings from rat isolated atria we studied the effects of Gd3+ (80 microM) on stretch-induced changes in action potentials. The stretch was induced by increasing pressure inside the atrium (1 mmHg to 7 mmHg). An elastic electrode holder that moved along the atrial tissue was used in the recordings. Thus the mechanical artifacts were eliminated and the cell-electrode contact was made more stable. To examine the influence of Gd3+ on atrial contraction we stretched the atria at different diastolic pressure levels (1 to 7 mmHg) with Gd3+ application of (80 microM) or diltiazem (5.0 microM). Contraction force was monitored by recording the pressure changes generated by the atrial contractions. 3. Our results show that: (1) atrial stretch induces delayed afterdepolarizations (DADs), increase in action potential amplitude and increase in relative conduction speed; (ii) Gd3+ blocks stretch-induced DADs and action potential changes; (iii) Gd3+ inhibits pressure-stimulated increase in the atrial contraction force, while similar inhibition is not observed with diltiazem, a blocker of L-type calcium channels. 4. This study suggests that Gd3+ inhibits stretch-induced changes in cell electrophysiology and contraction in the rat atrial cells and that the effects of gadolinium are due to rather specific block of stretch-activated ion channels with only a small effect on voltage-activated calcium channels.     

Impact of short‐term low‐dose atorvastatin on low‐density lipoprotein and high‐density lipoprotein subfraction phenotype

Statins can significantly reduce low‐density lipoprotein–cholesterol (LDL‐C) and modestly raise or not alter high‐density lipoprotein–cholesterol (HDL‐C). However, their impact on high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short‐term impact of low‐dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty‐seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL‐C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL‐C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.