lacidipine and Arteriosclerosis

Lacidipine, a third generation dihydropyridine calcium antagonist, has demonstrated pronounced anti-atherosclerotic activity in preclinical studies. The drug can act at several stages within the atherosclerotic process, utilising its antihypertensive and antioxidant properties to protect hypertensive animals against mortality and vascular damage, to reduce cholesterol levels from the vessel wall of hypercholesterolaemic animals, and to reduce the progression of existing atherosclerotic lesions. The clinical benefit of lacidipine in atherosclerosis has recently been confirmed in humans in a large, multicentre, comparative, 4-year clinical trial involving patients with mild to moderate hypertension. The European Lacidipine Study on Atherosclerosis (ELSA) showed that lacidipine was able to slow the progression of atherosclerosis, measured as carotid intimato-media thickness, by 40% compared with atenolol (p = 0.0073). Although further comparative trials are needed, based on the results of ELSA, lacidipine is likely to become a promising therapeutic agent for atherosclerosis.

Topics: Animals; Antioxidants; Arteriosclerosis; Calcium Channel Blockers; Cricetinae; Dihydropyridines; Endothelium, Vascular; Humans; Mice; Rabbits

Two key events in atherosclerotic plaque formation are the deposition of lipids in cells of the vascular wall, and migration and proliferation of arterial smooth muscle cells from the tunica intima toward the media. It has been shown that various calcium-channel antagonists may delay plaque formation in animal models. Among these, the new and highly lipophilic calcium antagonists, such as lacidipine and lercanidipine, display the most promising antiatherosclerotic activities. This paper will review and discuss these beneficial effects.

Topics: Arteriosclerosis; Calcium Channel Blockers; Cardiovascular System; Cell Division; Cell Movement; Dihydropyridines; Endothelium; Humans; Lipid Metabolism; Macrophages; Muscle, Smooth; Myocardium

Several calcium entry blockers have shown an antiatherosclerotic effect both in vitro and in vivo. The effects are particularly evident against smooth muscle cell migration multiplication, matrix formation, calcium and cholesterol accumulation. Among the new calcium antagonists, isradipine, amlodipine and lacidipine, are promising as antiatherosclerotic agents. Lacidipine is particularly interesting because of its lipophylic structure and accumulation in cell membranes. Lacidipine is structurally related to nifedipine; we observed that lacidipine inhibits three major processes of atherogenesis: cholesteryl ester metabolism in macrophages, proliferation of myocytes, and their migration.

Topics: Animals; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cell Division; Cell Movement; Dihydropyridines; Humans

Topics: Antihypertensive Agents; Arteriosclerosis; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Hypertrophy, Left Ventricular; Multicenter Studies as Topic

To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints.. In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Topics: Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

It has been known for some time that calcium antagonists demonstrate antiatherosclerotic activity. These agents have been shown to reduce the extension of atherosclerotic lesions in cholesterol-fed rabbits without affecting plasma lipid concentrations or blood pressure, suggesting a direct protective effect on the arterial wall. Lacidipine is a recently developed dihydropyridine calcium antagonist that is extremely lipophilic and has potent and long-lasting antihypertensive properties. Lacidipine directly inhibits the enzyme, acylcoenzyme A-cholesterol acyltransferase, and affects intracellular cholesterol homeostasis by preventing acetyl low-density lipoprotein cholesterol esterification. In vivo studies have shown that lacidipine also reduces the intimal hyperplasia induced by insertion of a plastic collar around one carotid artery in cholesterol-fed rabbits. In animals treated with lacidipine, the rapid proliferation of smooth-muscle cells inside the carotid wall is totally inhibited. Lacidipine, therefore, appears to protect the arterial wall against the development of atherosclerotic lesions in animal or human subjects with severe and multiple risk factors. It seems likely that these effects are achieved by a direct action on the mechanisms involved in atherogenesis.

Topics: Animals; Arteriosclerosis; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Muscle, Smooth, Vascular

Membrane-active drugs can be characterized by direct measurements of their membrane partition coefficients, washout rates from membranes, and washin rates into membranes. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. Lacidipine has a high membrane partition coefficient compared to other 1,4-dihydropyridine calcium-channel antagonists and a slow washout rate from membranes. Clinically, it also exhibits an extended duration of action. This control at the membrane molecular level may provide an optimal pharmacokinetic profile for lacidipine in the treatment of hypertension. In addition, these same properties may be important for lacidipine as an antiproliferative agent in the treatment of atherosclerosis.

Topics: Animals; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Membranes

The European Lacidipine Study on Atherosclerosis (ELSA) has been planned to investigate the effect of reduction in office and ambulatory blood pressure by lacidipine versus atenolol on carotid artery wall thickness in mild to moderate essential hypertensive patients with no metabolic abnormalities. One prespecified sub-study of ELSA focused on measurements of arterial distensibility in the carotid as well as in the radial artery to determine the relationship of functional arterial properties with office versus ambulatory blood pressure (BP) values as well as the correspondence between functional and structural arterial alterations.. The sub-study was conducted on 124 patients recruited in four centres (Monza-Milan, Paris, Grenoble and Glasgow). BP was measured both by a mercury sphygmomanometer and by 24-h ambulatory monitoring. Common carotid artery wall thickness was measured by certified sonographers as described in the main study. Common carotid and radial artery distensibility were obtained by echotracking techniques, which allowed to relate changes in arterial diameter with systo-diastolic BP changes.. Carotid artery wall distensibility showed (1) a negative correlation with office and more so 24-h average systolic BP (r = -0.45 and -0.58, P < 0.008 and 0.001) but not with office or 24-h diastolic BP) and (2) a negative correlation with the corresponding wall thickness (r = -0.47, P < 0.005). In contrast, at the radial artery level distensibility and thickness showed no correlation with each other and with BP. Carotid (but not radial) artery distensibility also correlated with ambulatory systolic BP variability but the correlation was lost after adjustment for age and mean BP values.. These data suggest that stiffening of large elastic artery is reflected more by ambulatory than office BP elevations, systolic BP being much more important than diastolic. Alterations of large elastic arteries function is related to structural wall changes. Functional and structural properties of middle-size muscle arteries are independent of BP.

Topics: Antihypertensive Agents; Arteriosclerosis; Atenolol; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Carotid Artery, Common; Circadian Rhythm; Dihydropyridines; Europe; Female; Humans; Hypertension; Male; Middle Aged; Radial Artery; Ultrasonography

Baseline data from the European Lacidipine Study on Atherosclerosis (ELSA) have shown that carotid intima-media thickness (IMT) is not related to diastolic blood pressure (BP), but that it is related to clinic systolic (S) or pulse pressure (PP) and more so to their 24 h average values. The aim of the present study was to determine whether IMT independently relates to additional information obtained through ambulatory BP, in particular to SBP or PP variability.. In 1663 hypertensive patients, after a wash-out period from antihypertensive treatment (mean age 56.2 +/- 7.65 years), IMT was assessed from 12 different carotid sites. Ambulatory BP measurements were performed every 15 min (day) and every 20 min (night). IMT values were positively related to 24 h, day and night average SBP and PP. There was some relationship of IMT with day-night or clinic-day SBP and PP differences. The most important finding, however, was that IMT values were related with 24 h SBP or PP standard deviation (P < 0.001), a measure of overall SBP or PP variability. The relationship was seen also by multiple regression analysis, the standard deviation for SBP or PP only following age and 24 h average SBP or PP in accounting for IMT values.. This is the first demonstration from a large database that not only average 24 h PP and SBP values, but also 24 h BP fluctuations, are associated with, and possibly determinants of, the alterations of large artery structure in hypertension.

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Carotid Arteries; Cross-Sectional Studies; Dihydropyridines; Humans; Hypertension; Middle Aged; Prospective Studies; Pulse; Tunica Intima; Tunica Media; Ultrasonography

The European Lacidipine Study of Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multi-national interventional trial to determine the effect of four-year treatment using the calcium antagonist lacidipine versus the beta-blocker atenolol on the progression of carotid atherosclerosis in 2259 asymptomatic hypertensive patients. B-mode ultrasound is used to measure the primary and secondary endpoints including the mean maximum intima-media thickness (IMT) of the carotid bifurcations and the common carotid arteries (CBM(max)), the mean maximum IMT of 12 standard carotid sites (M(max)) and the overall maximum IMT (T(max)). This paper reports the cross-sectional reproducibility of ultrasound measurements at baseline.. To evaluate measurement reliability, each patient is scanned twice at baseline and again at four annual visits, with 80% of the replicate scans performed by the same sonographer and 20% by a different sonographer; 50% of the replicate scans are read by the same reader and the other 50% by different readers.. The overall coefficient of reliability (R) was 0.859 for CBM(max), 0.872 for M(max) and 0.794 for T(max). The reliability for CBM(max) was stable during the 1 3/4-year baseline period (R = 0.848 to 0.953) and was uniform among the 23 field centres (R = 0.798 to 0.926). Intra- and inter-reader reliability were 0.915 and 0.872 respectively, and intra-sonographer reliability was 0.866.. The results demonstrate that by implementing standardized protocols and strict quality control procedures, highly reliable ultrasonic measurements of carotid artery IMT can be achieved in large multi-national trials.

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Double-Blind Method; Europe; Humans; Observer Variation; Prospective Studies; Quality Control; Reproducibility of Results; Ultrasonography

The possibility that calcium antagonists exert an anti-atherosclerotic action at least partly independently of the blood-pressure-lowering effect is supported by results of a large number of experimental studies and can now be investigated by quantitative B-mode ultrasound imagining of the carotid artery walls.. The European Lacidipine Study on Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multinational trial comparing effects of 4-year treatment based on the long-acting, highly lipophilic calcium antagonist lacidipine with those of treatment based on the beta-blocker atenolol on the development of carotid artery wall alterations in patients (aged 45-75 years) with mild-to-moderate hypertension (systolic blood pressure 150-210 mmHg and diastolic blood pressure 95-115 mmHg). While the intervention study is progressing, this article summarizes baseline data obtained from the whole cohort of 2259 patients randomly allocated to treatment.. Baseline ultrasound data were obtained from two replicate examinations performed shortly before random allocation to treatment by certified sonographers at 23 referral centres and read at the ultrasound coordinating centre at the Wake Forest University School of Medicine. Intima-media thickness was measured at up to 12 different sites in the carotid artery tree and expressed as the mean of the maxima at these sites (Mmax), the mean of the maxima at four sites in the distal common carotid artery and bifurcation (CBMmax) and the maximum intima-media thickness (Tmax). Baseline demographic and clinical measurements were performed by investigators in 410 peripheral clinical units and 24 h ambulatory blood pressure monitorings read and validated by members of a centralized unit at the University of Milan. The statistical analysis centre at the Technische Universität München received and analysed all baseline data, by calculating means +/- SD, medians and ranges and performing correlation (Spearman correlation coefficients) and multiple regression analyses.. Prevalence of carotid artery wall alterations among the hypertensive patients randomly allocated to treatment in the ELSA was very high: 82% had Tmax > or = 1.3 mm ('plaques' according to protocol) and 17% had Tmax > or = 1.0 and < 1.3 mm ('thickening'), with a median of two plaques per patient. We found significant correlations between ultrasound measurements and the following demographic and clinical variables: age, sex, systolic blood pressure and pulse pressure (both clinic and ambulatory), concentrations of total, high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides, smoking habit and duration of hypertension. We found no significant correlation to diastolic blood pressure and glucose concentration. A multiple regression analysis indicated significant variables in the following rank order: age, 24 h ambulatory pulse pressure, sex, low-density lipoprotein cholesterol concentration, triglyceride concentration, smoking and clinic systolic blood pressure.. Analysis of baseline data from the ELSA has shown that there is an extremely marked prevalence of carotid artery wall alterations among mild-to-moderate, middle-aged hypertensive patients. In addition to age, systolic blood pressure and pulse pressure, particularly if they are accurately measured by ambulatory monitoring, play a major role, somewhat greater than those of sex, low-density lipoprotein cholesterol concentration and smoking, in influencing intima-media thickness.

Topics: Adrenergic beta-Antagonists; Aged; Arteriosclerosis; Atenolol; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Carotid Arteries; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Ultrasonography

The European Lacidipine Study on Atherosclerosis (ELSA) is a multinational interventional clinical trial aimed at determining the antiatherosclerotic effects of Lacidipine, a calcium antagonist, when compared to atenolol, a beta-blocker, on the carotid arteries of 2300 cardiovascular asymptomatic patients with moderately high blood pressure. Quantitative B-mode ultrasound imaging is being used to measure the intima-media thickness of a standardized section of the carotid arteries including the distal common, bifurcation, and proximal internal carotids. Prospective investigations of large samples of population using ultrasonographic endpoints rely heavily on the precision and reproducibility of the method. Therefore, specific quality control protocols are required to determine and monitor cross-sectional and longitudinal stability of the measurement reproducibility. In ELSA, the ultrasound methodology was specifically designed to include a set of procedures to quality control the critical components of measurement variation including instrumentation, and ultrasound operators, i.e. sonographers and readers. The ELSA clinical trial will provide the largest set of prospective quality control data on the use of quantitative B-mode ultrasound imaging.

Topics: Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Ultrasonography

In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid wall alterations are assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the intima-media thickness of the carotid artery wall, measured with B-mode ultrasound. About 2300 hypertensive patients have been recruited and randomized to either of the antihypertensive agents. Baseline data for 1965 patients are available, showing a high prevalence of carotid wall lesions: about 82% of the subjects have an intima-media thickness > or = 1.3 mm, defined as plaque in the ELSA protocol; 16% of the subjects have intima-media thickening (> or = 1.0 mm, < 1.3 mm) and only about 1% have normal carotid artery walls. Analysis of demographic data and risk factor prevalence in ELSA patients, and comparison of these preliminary observations with data from other intervention or observational studies indicate that high blood pressure is a very important risk factor for carotid atherosclerosis.

Topics: Antihypertensive Agents; Arteriosclerosis; Carotid Artery Diseases; Dihydropyridines; Europe; Female; Humans; Hypertension; Male; Middle Aged; Prevalence

Topics: Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Humans

Topics: Antihypertensive Agents; Arteries; Arteriosclerosis; Compliance; Dihydropyridines; Humans

Up to the present the relationship between arterial hypertension or its treatment and cardiovascular complications has been evaluated in terms of the incidence of events, such as fatal and nonfatal myocardial infarction or stroke and cardiac deaths. However, cardiovascular events are not the direct consequence of blood pressure elevation, which, on the contrary, is responsible for atherosclerotic disease. Quantitative ultrasonography is a sensitive, specific and reproducible technique which, in comparison to arteriography, is non invasive and less expensive. The availability of this technique has allowed us to do some studies, one just published, another in the elaboration phase and others ongoing, aimed at evaluating the effects of antihypertensive agents on carotid changes in hypertensive patients. The European Lacidipine Study on Atherosclerosis (ELSA) compares the effects of lacidipine, a calcium-antagonist and of atenolol, a beta-blocker, on blood pressure, on carotid vessel modifications, and on the incidence of cardiovascular events in patients with mild to moderate hypertension with a 4-year follow-up period. Preliminary results of the study, which were concerned with the demographic characteristics of the first 1000 randomized patients enrolled, indicate that 84% of the patients had a carotid plaque, 15% had thickening of the intima-media, and 1% had a normal vessel. These results are both surprising and significant in that they admonish the physician not to neglect patients with mild to moderate hypertension even when they have neither complications nor other risk factors.

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Carotid Artery Diseases; Delayed-Action Preparations; Dihydropyridines; Double-Blind Method; Europe; Humans; Hypertension; Middle Aged

To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints.. In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Topics: Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

The European Lacidipine Study on Atherosclerosis (ELSA) has been designed to compare the effects of two antihypertensive agents, the calcium antagonist lacidipine and the beta-blocker atenolol, on the development of atherosclerosis in hypertensive patients stratified according to the presence of carotid plaques, or the presence or absence of carotid artery intima-media thickening. ELSA is a multinational, multicenter, randomized, double-blind, parallel group study that is to be conducted over a 5-year period. Recruitment and treatment will take place at 23 referral centers in seven countries. A total cohort of 3,660 patients, aged between 45 and 75 years, with diastolic blood pressure 95-115 mm Hg and systolic blood pressure < or = 210 mm Hg at enrollment, will be stratified into three groups according to a B-mode ultrasound analysis of the carotid wall morphology. After a 1-month placebo run-in period, patients will be randomized to receive either lacidipine (4-6 mg once daily) or atenolol (50-100 mg once daily). Nonresponders will be treated with hydrochlorothiazide (12.5 mg, eventually titrated to 25 mg if required), on an open basis. During the course of the study, patients will be monitored by carotid ultrasound assessment and ambulatory blood pressure monitoring. The results of this study should further understanding of the pathobiology of atherosclerosis, and its development and prevention.

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Double-Blind Method; Europe; Humans; Hypertension; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Ultrasonography

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Middle Aged

A study has been carried out in the apolipoprotein (apo) E-deficient mouse to investigate the activity of lacidipine (a calcium antagonist with antioxidant properties) in inhibiting the development of atherosclerotic lesions; of particular interest were changes in the susceptibility of low-density lipoproteins (LDL) to oxidation. Mice receiving a Western-type diet to accelerate the development of atherosclerosis were treated orally with vehicle or lacidipine at 3 or 10 mg/kg/day for 8 weeks. Lacidipine treatment (at 3 or 10 mg/kg) had no effect on the plasma lipid profile. However, a significant (P < 0.01) dose-related reduction of 43 and 50% of the aortic lesion area in respect to vehicle-treated mice was observed. Moreover, the resistance of mouse plasma LDL to undergo lipid peroxidation was significantly (P < 0.01) increased in apo E-deficient mice treated with lacidipine. The native LDL-like particle, derived from apo E-deficient mice treated with lacidipine, contained significantly lower concentrations of malonyldialdehyde than the vehicle-treated control group (P < 0.01). After exposure to human umbilical vein endothelial cells, LDL-like particle vitamin E levels (expressed as area under the curve; AUC), were significantly higher (P < 0.01) in both the 3 and 10 mg/kg lacidipine-treated groups, in comparison with the vehicle-treated control animals. We conclude that lacidipine reduced the extent of the atherosclerotic area in hypercholesterolaemic apo E-deficient mice, and that this reduction may be associated with the capacity of the drug to decrease the susceptibility of LDL to oxidation.

Topics: Animals; Antioxidants; Apolipoproteins E; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Disease Susceptibility; Dose-Response Relationship, Drug; Female; Lipid Peroxidation; Lipoproteins, LDL; Malondialdehyde; Mice; Mice, Knockout; Random Allocation; Vitamin E

Topics: Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Randomized Controlled Trials as Topic; Tunica Intima; Tunica Media

Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Humans; Hypertension; Randomized Controlled Trials as Topic

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Carotid Stenosis; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors; Ultrasonography, Doppler, Color

We have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins; these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 +/- 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells; lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Calcium Channel Blockers; Cholesterol; Cholesterol, Dietary; Cricetinae; Dihydropyridines; Disease Models, Animal; Lipids; Lipoproteins; Male; Mesocricetus

Lacidipine is a widely used calcium-channel blocker, which has both long-lasting antihypertensive activity and also antioxidant properties. Previous studies have demonstrated the ability of lacidipine to reduce the development of atherosclerotic lesions in several animal models.. The present study investigated the antiatherosclerotic potential of lacidipine in the apoE-deficient mouse, an experimental model of atherosclerosis showing progressively complex and widespread lesions which closely resemble the inflammatory-fibrous plaques seen in humans.. Lacidipine was administered daily by gavage for 10 weeks at dose levels of 0 (control), 0.3, 1.0 and 3.0 mg/kg.. Lacidipine administration reduces the extension of atherosclerotic lesions in the aorta of the apoE-deficient mouse without affecting plasma lipid levels. We also show that apoE-deficient mice have four-fold higher values of the proatherogenic peptide, endothelin, compared with the wild-type C57BL/6 mouse and that lacidipine administration reduced, in a dose-dependent manner, the concentrations of plasma endothelin.. Lacidipine has anti-atherogenic effects in the apoE-deficient mouse, and reduces plasma endothelin concentrations.

Topics: Animals; Antihypertensive Agents; Apolipoproteins E; Arteriosclerosis; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Dose-Response Relationship, Drug; Endothelins; Female; Mice

The mechanisms by which oxidized low-density lipoprotein (ox-LDL) induces the expression of adhesion molecules on endothelial cells (HUVECs) are still not clear. The signal transduction pathways for these binding molecules include the translocation of the transcription factor NF-kB and the intracellular reactive oxygen species (ROS) are said to play a key role in this process. Aim of this study was (1) to evaluate the effect of ox-LDL on intracellular production of ROS in culture of HUVECs; (2) to evaluate if the intracellular increase of ROS induced by ox-LDL is mediated by the binding to a specific endothelial receptor; (3) to ascertain if lacidipine can decrease ox-LDL-induced ROS production in HUVECs.. Five microM Cu2+ ox-LDL were incubated with HUVECs for 5 min. 2',7'-Dichlorofluorescein (DCF) as an expression of intracellular ROS production, was measured by flow cytometry.. ox-LDL induced a significant dose-dependent increase in DCF production (P < 0.001) through the binding to a specific receptor. The preincubation of HUVECs with radical scavengers compounds and lacidipine significantly reduced (P < 0.001) the ox-LDL-induced DCF production.. ox-LDL increased the intracellular formation of ROS through the ligation to a specific endothelial receptor. Preincubation of HUVECs with lacidipine, a calcium antagonist with antioxidant properties, significantly reduced the intracellular ROS formation induced by ox-LDL. We propose that the effect of lacidipine on adhesion molecule expression and on NF-kB activation can be explained by its effect on intracellular ROS formation.

Topics: Antioxidants; Arteriosclerosis; Calcium Channel Blockers; Cell Adhesion Molecules; Cells, Cultured; Dihydropyridines; Endothelium, Vascular; Fluoresceins; Fluorescent Dyes; Humans; Intracellular Fluid; Lipoproteins, LDL; NF-kappa B; Oxidation-Reduction; Reactive Oxygen Species

The in vivo antiatherogenic activity of two calcium antagonists of the dihydropyridine class (isradipine and lacidipine) was investigated in a new experimental model. The proliferative lesion induced in the rabbit carotid artery was obtained by positioning a hollow silastic collar around the vessel. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries obtained 14 days after collar placement. The effectiveness in inhibiting neointimal formation was assessed for isradipine (0.5, 1 and 4 mg kg-1 day-1) in normocholesterolemic (NC) animals and for lacidipine (1, 3, and 10 mg kg-1 day-1) in hypercholesterolemic (HC) rabbits. In NC control animals a neointimal formation was clearly detectable (I/M 0.53 +/- 0.18, n = 5). In isradipine-treated groups I/M ratios were significantly decreased (0.15 +/- 0.03, 0.12 +/- 0.02, 0.1 +/- 0.02 for the 0.5, 1 and 4 mg kg-1 day-1 doses respectively). In HC rabbits the administration of cholesterol 1% mixed with food and drug treatment started either 60 days before collar insertion (pretreated group, HC60) or on the same day (non pretreated group, HC15) of the collar placement. Only the pharmacological pretreatment was effective in reducing neointimal formation (0.47 +/- 0.02, 0.4 +/- 0.09, and 0.32 +/- 0.02 for dose 1, 3 and 10 mg kg-1 day-1 vs 1.1 +/- 0.14 in control animals). The inhibition of neointimal hyperplasia was much less evident in nonpretreated animals (0.7 +/- 0.15, 0.6 +/- 0.18 and 0.43 +/- 0.08 for dose 1, 3, and 10 mg kg-1 day-1 vs 0.72 +/- 0.2 in control animals). These results suggest a direct antiatherosclerotic effect of isradipine and lacidipine on neointimal hyperplasia induced in NC and HC pretreated rabbits independently of modulation of risk factors such as hypercholesterolemia and/or hypertension.

Topics: Animals; Arteriosclerosis; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Dose-Response Relationship, Drug; Hypercholesterolemia; Isradipine; Male; Muscle, Smooth, Vascular; Neovascularization, Pathologic; Rabbits

1. The in vivo antiatherogenic activity of the calcium antagonist, lacidipine, was investigated in two different types of atherosclerotic lesions (proliferative and fatty lesions) induced in rabbits. 2. The proliferative lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty lesions were induced by cholesterol feeding. Cholesterol (1%) and lacidipine (1, 3, and 10 mg kg-1) were given daily mixed with standard diet for 8 weeks to White New Zealand rabbits. The intimal hyperplasia (proliferative lesion) was induced 6 weeks after dietary and drug treatment started. 3. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals (n = 5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries with no collar (sham) showed an I/M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.62 +/- 0.12. In lacidipine-treated animals a significant and dose-dependent effect on proliferative lesions at all three doses tested, was observed. I/M ratios were 0.47 +/- 0.02, 0.40 +/- 0.09, 0.32 +/- 0.02 for doses 1, 3, and 10 mg kg-1 day-1, respectively (P < 0.05). 4. The fatty lesion extent was significantly reduced by lacidipine at the 10 mg kg-1 day-1 dose, although a trend was also observed with lower dosage. 5. These results suggest a direct antiatherosclerotic effect of lacidipine, independent of modulation of risk factors such as hypercholesterolaemia and/or hypertension. Furthermore, the proliferative lesions are apparently more sensitive to lacidipine than are lipid-rich lesions.

Topics: Animals; Aorta; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Hypercholesterolemia; Hyperplasia; Lipids; Male; Rabbits

Topics: Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Multicenter Studies as Topic; Statistics as Topic

The in vivo antiatherogenic activity of the calcium antagonist lacidipine was investigated in arterial hyperplasia induced by perivascular manipulation of hypercholesterolemic carotid rabbits. This was accomplished by positioning a hollow silastic collar around one carotid, which within a few days induces an atherosclerotic lesion (proliferative lesion) showing biochemical and morphologic changes similar to those of early human atherosclerosis: the contralateral carotid, with no collar, served as control in the same animal. The effect of lacidipine was also investigated in aortic atherosclerotic lesions (fatty lesions) induced by hypercholesterolemia mixed with either cholesterol (1%) and lacidipine (3 mg/kg/day) or cholesterol (1%) alone for 8 weeks. Hypercholesterolemic New Zealand White rabbits were fed daily a standard diet. Intimal hyperplasia was mechanically induced in one carotid artery of each rabbit 6 weeks after dietary and drug treatment started. Neointimal formation was followed by measuring by light microscopy the cross-sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In positive control animals receiving dietary cholesterol only (n = 10), by 14 d after collar positioning the process of intimal hyperplasia was significantly pronounced. The control arteries showed an I:M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.56 +/- 0.11. In the animals receiving lacidipine, neointimal formation was significantly lower [I:M tissue ratio 0.32 +/- 0.1 (n = 10), about 60% of positive controls]. Measurement of the percent area of the aortic intima covered by plaques did not show significant differences between control and lacidipine-treated animals. These results suggest a direct antiatherosclerotic effect of lacidipine on proliferative lesions.

Topics: Animals; Aorta; Aorta, Thoracic; Arteriosclerosis; Calcium Channel Blockers; Carotid Arteries; Carotid Artery Injuries; Cholesterol; Diet, Atherogenic; Dihydropyridines; Hyperplasia; Male; Rabbits

To evaluate the effect of lacidipine on the major processes of atherogenesis.. Cell-culture methods were used to study the effect of lacidipine. Low-density lipoprotein (LDL) receptor expression and cholesterol esterification were evaluated in human skin fibroblasts and in mouse peritoneal macrophages, respectively. The effect of lacidipine on cellular proliferation was tested on aortic myocytes cultured from rat aorta.. Lacidipine did not affect LDL receptor expression, but it inhibited the ability of acetyl LDL to stimulate cholesterol esterification in macrophages by more than 95%. The drug inhibited cellular proliferation in a dose-dependent manner. This antiproliferative effect was confirmed in human femoral artery myocytes. In accord with the inhibitory effect on cellular growth, preliminary in vivo studies suggest that lacidipine may reduce neointimal formation induced by perivascular manipulation of the carotid artery in hypercholesterolemic rabbit.. Our results indicate that lacidipine may be antiatherosclerotic through an effect on the major processes involved in atheroma formation.

Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Cell Division; Cells, Cultured; Cholesterol Esters; Dihydropyridines; Esterification; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Receptors, LDL