dihydropyridines has been researched along with Arteriosclerosis* in 60 studies
12 review(s) available for dihydropyridines and Arteriosclerosis
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Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research.
Atherosclerosis is a systemic disease that can ultimately lead to ischaemia and infarction in the heart, brain and peripheral vasculature. According to the "response to injury" hypothesis, endothelial dysfunction is the early event that allows penetration of lipids and inflammatory cells into the arterial wall, contributing to the development of the atherosclerotic lesion. Endothelial dysfunction is causally related to a variety of risk factors for atherosclerosis, including hyperlipidaemia and hypertension. Agents that restore endothelial function and NO bioavailability have beneficial anti-atherogenic activities and can improve cardiovascular outcomes; this has been observed with angiotensin-converting enzyme (ACE) inhibitors, statins and certain dihydropyridine-type calcium channel blockers (CCBs). In the Prospective Randomised Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the CCB amlodipine provided significant clinical benefits compared with placebo, including a marked reduction in cardiovascular morbidity and a reduction in the progression of carotid atherosclerosis. As these beneficial effects of amlodipine have not been observed with other dihydropyridine-type CCBs, it has been proposed that this agent has distinct anti-atherosclerotic properties related to its strong lipophilicity and membrane location. Experimental support for this hypothesis has been obtained from various in vitro and in vivo models of atherosclerosis. These findings support a broader therapeutic role for third-generation dihydropyridine-type CCBs in the treatment of atherosclerosis. Topics: Arteriosclerosis; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Humans; In Vitro Techniques; Models, Cardiovascular; Randomized Controlled Trials as Topic; Time Factors | 2003 |
Vascular protective effects of dihydropyridine calcium antagonists. Involvement of endothelial nitric oxide.
Dihydropyridine calcium antagonists play an important role in the treatment of hypertension and angina pectoris. They lower blood pressure by a well-characterized mechanism of blocking L-type calcium channels in smooth muscle cells. Additionally, there is growing evidence that dihydropyridines also modulate endothelial functions by other mechanisms, since macrovascular endothelial cells do not express L-type calcium channels. A number of studies have demonstrated that dihydropyridine calcium antagonists enhance bioavailability of endothelial nitric oxide (NO). Endothelium-derived NO plays a pivotal role in the regulation of vasorelaxation, leukocyte adhesion and platelet aggregation and an impaired NO release is associated with the genesis and progression of atherosclerotic diseases. This review summarizes results from experimental findings that dihydropyridine calcium antagonists increase endothelial NO formation as well as studies which demonstrate these effects in vivo both in animals and humans. Moreover, the influence of dihydropyridine calcium antagonists on the progression of atherosclerosis is discussed. These pleiotropic effects of dihydropyridine calcium antagonists may underlie or contribute to antiatherosclerotic effects of this substance class. Topics: Animals; Arteriosclerosis; Biological Availability; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Humans; Nitric Oxide; Nitric Oxide Synthase | 2003 |
Endothelial dysfunction, hypertension and atherosclerosis. A review of the effects of lacidipine.
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 | 2002 |
Vatanidipine hydrochloride: a new long-lasting antihypertensive agent.
Vatanidipine is a novel dihydropyridine (DHP)-type calcium channel blocker with slow-onset pharmacological actions, which are probably due to both its slow uptake into vascular tissues and resistance in its approach to the calcium channel binding site. Vatanidipine once incorporated into vascular tissues is not easily released, even by repeated washing, thus resulting in a long-lasting action of the agent. A slow-onset and long-lasting hypotensive action was observed in various experimental hypertensive models. Clinical trials using human subjects with essential hypertension indicated that vatanidipine exerts an antihypertensive effect with a slow onset and long duration. In spite of its potent hypotensive effect, the incidence of adverse effects by vatanidipine administration has been reported to be lower than that in cases of nitrendipine. In addition to its vasodilatory effects, vatanidipine efficiently suppressed noradrenaline release from sympathetic nerve endings, thus suggesting this agent exhibits a beneficial effect in the treatment of hypertensive patients, in which the reflex activation of peripheral sympathetic nerves is unfavourable to antihypertensive therapy. In a double-blind study, vatanidipine did not show reflex tachycardia, despite producing a potent and long-lasting hypotensive effect, in contrast to the administration of nitrendipine. In an animal study, vatanidipine exhibited a protective effect against cerebrovascular lesions, through a mechanism independent of its hypotensive effect. In addition, a renoprotective effect was also observed in experimental hypertensive models. In cholesterol-fed rabbits, vatanidipine exerted an anti-atherosclerotic action, which is probably attributable to the inhibitory action of the agent on low-density lipoprotein oxidation. In essential hypertensive patients, the plasma levels of cholesterol and triglyceride decreased after vatanidipine treatment, thus suggesting that this agent may have a therapeutic potential in preventing such vascular diseases as atherosclerosis. Taken together, vatanidipine appears to be a novel and useful antihypertensive agent, which can both prevent target-organ damage and reduce cardiovascular morbidity and mortality. Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Nitrendipine | 2001 |
Lipophilic calcium antagonists in antiatherosclerotic therapy.
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 | 2000 |
Calcium, calcium antagonists and experimental atherosclerosis.
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 | 1996 |
Hypertension, atherosclerosis and LVH in ELSA. European Lacidipine Study of Atherosclerosis.
Topics: Antihypertensive Agents; Arteriosclerosis; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Hypertrophy, Left Ventricular; Multicenter Studies as Topic | 1996 |
Evaluating the benefits of an antihypertensive agent using trials based on event and organ damage: the Systolic Hypertension in the Elderly Long-term Lacidipine (SHELL) trial and the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 1995 |
The antiatherosclerotic effects of calcium antagonists.
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 | 1995 |
The molecular basis for lacidipine's unique pharmacokinetics: optimal hydrophobicity results in membrane interactions that may facilitate the treatment of atherosclerosis.
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 | 1994 |
Antiatherosclerotic actions of isradipine.
Isradipine, a calcium antagonist of the dihydropyridine type, shows antiatherosclerotic actions that interfere with all three main mechanisms of atherosclerosis. These actions are mediated by the release of prostaglandin I2 and endothelium-derived relaxing factor, and the subsequent elevation of intracellular adenosine-3',5'-cyclic phosphate and 3',5'-guanosine monophosphate, respectively. These mechanisms have been proven in vitro and in animal models. Preliminary data in humans suggest that these mechanisms have clinical relevance in the long-term treatment of patients as well. Topics: Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Isradipine; Lipid Metabolism | 1992 |
Antiatherogenic properties of calcium antagonists. State of the art.
Atherosclerosis is an arterial disease characterized by localized accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolism. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium antagonists can reduce the accumulation of atherogenic lesion components and decrease the progression of lesions. Although there are some conflicting data in the animal model studies, it is now apparent that several classes of calcium antagonists inhibit the progression of early arterial lesions induced by cholesterol-feeding in animals. The dihydropyridine class of calcium antagonists may be more potent as anti-atherosclerotic agents than the other classes. Mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolism may be responsible for the effects of calcium antagonists on early lesion progression. Recent studies in cell culture-model systems suggest that calcium antagonists may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by arterial wall cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium antagonists may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium channel-independent metabolic activities, which affect lesion development. Topics: Animals; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cells, Cultured; Cholesterol; Dihydropyridines; Humans | 1989 |
15 trial(s) available for dihydropyridines and Arteriosclerosis
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Different relation between 24-h blood pressure and distensibility at different peripheral arteries. Data from the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 2005 |
Relation between blood pressure variability and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 2001 |
Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 2000 |
Improvement of insulin resistance in essential hypertension by long-acting Ca antagonist benidipine.
To investigate whether the long-acting Ca channel blocker, benidipine improves insulin resistance in patients with essential hypertension, insulin sensitivity was measured using the steady state plasma glucose (SSPG) method in 11 or 14 nonobese and nondiabetic hypertensive subjects before and after treatment with benidipine or placebo, respectively, and 11 healthy control subjects. SSPG level was significantly higher in two hypertensive groups, indicating reduced insulin sensitivity than in controls. SSPG level significantly decreased after benidipine treatment, with a decrease of blood pressure. SSPG level and blood pressure did not change in the placebo group. As for oral glucose tolerance test, the area under the curve of insulin diminished significantly after benidipine treatment. SSPG level significantly correlated with intra-platelet Ca2+ concentrations in 9 hypertensive subjects. The long-acting Ca channel blocker benidipine has partially improved insulin resistance in essential hypertension, contributing to the prevention of atherosclerosis associated with insulin resistance. Topics: Apolipoproteins; Arteriosclerosis; Blood Glucose; Blood Platelets; Blood Pressure; Calcium; Calcium Channel Blockers; Catecholamines; Dihydropyridines; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Intracellular Fluid; Male; Middle Aged; Treatment Outcome | 1999 |
Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis.
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 | 1998 |
Ultrasound protocol and quality control procedures in the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 1996 |
Prevalence of carotid atherosclerosis in hypertension: preliminary baseline data from the European Lacidipine Study on Atheroscelerosis (ELSA).
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 | 1996 |
Ambulatory blood pressure monitoring in the ELSA study. European Lacidipine Study on Atherosclerosis.
Topics: Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Humans | 1996 |
Compliance studies in ELSA. European Lacidipine Study of Atherosclerosis.
Topics: Antihypertensive Agents; Arteries; Arteriosclerosis; Compliance; Dihydropyridines; Humans | 1996 |
[The preliminary clinical evidence from the ELSA study. The European Lacidipine Study on Atherosclerosis].
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 | 1995 |
Evaluating the benefits of an antihypertensive agent using trials based on event and organ damage: the Systolic Hypertension in the Elderly Long-term Lacidipine (SHELL) trial and the European Lacidipine Study on Atherosclerosis (ELSA).
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 | 1995 |
Potential modification of plaque behavior through the European lacidipine study on atherosclerosis.
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 | 1995 |
The E.L.S.A. trial: protocol of a randomized trial to explore the differential effect of antihypertensive drugs on atherosclerosis in hypertension.
Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Middle Aged | 1994 |
MIDAS: hypertension and atherosclerosis. A trial of the effects of antihypertensive drug treatment on atherosclerosis. MIDAS Research Group.
Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke, the reduction in coronary artery disease mortality has been less impressive. It may be that the antihypertensive drugs used in these trials induced metabolic disturbances, or produced inadequate regression of left ventricular hypertrophy, thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering. Isradipine, a dihydropyridine calcium antagonist known to be an effective antihypertensive agent, has also displayed pronounced antiatherogenic effects in animals. Thus, a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure, but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries, thereby leading to prevention of clinical sequelae of atherosclerosis. On this basis, a 3-year clinical trial is being carried out in the United States--the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)--to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients. The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries, as measured by B-mode ultrasonography. Topics: Antihypertensive Agents; Arteriosclerosis; Dihydropyridines; Double-Blind Method; Female; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Male | 1992 |
The Multicenter Isradipine/Diuretic Atherosclerosis Study: a study of the antiatherogenic properties of isradipine in hypertensive patients. MIDAS Research Group.
Hypertension is a risk factor for the development of atherosclerosis and its complications, which are among the major causes of morbidity and mortality. Although recent clinical trials indicate that antihypertensive treatment reduces morbidity and mortality associated with stroke, congestive heart failure, and renal insufficiency, questions remain as to whether such treatment also prevents coronary heart disease (CHD) mortality. The observed reduction in CHD mortality from pooled clinical trial data was 10-14% and was much less than the expected 20-25% reduction for a 5-6 mm Hg reduction in diastolic pressure. One explanation may be that subtle adverse metabolic effects of treatment may have blunted the beneficial effects. Isradipine, a dihydropyridine calcium antagonist, is a potent antihypertensive drug with antiatherogenic properties in animal models. Therefore, we hypothesized that isradipine may be appropriate for testing the efficacy of antihypertensive treatment in retarding the progression of atherosclerosis in humans. The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a clinical trial designed to compare the efficacy of isradipine (2.5 or 5 mg b.i.d.) with hydrochlorothiazide (12.5 or 25 mg b.i.d.) in retarding the progression of early carotid atherosclerosis as monitored by high-resolution B-mode ultrasonography. Topics: Adult; Aged; Arteriosclerosis; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Double-Blind Method; Female; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Male; Middle Aged; Ultrasonography | 1991 |
34 other study(ies) available for dihydropyridines and Arteriosclerosis
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Clinical study with azelnidipine in patients with essential hypertension. Antiarteriosclerotic and cardiac hypertrophy-inhibitory effects and influence on autonomic nervous activity.
A dihydropyridine calcium (Ca) antagonist, azelnidipine (CAS 123524-52-7, Calblock), exhibits hypotensive effects for a prolonged duration, and has been reported to have a strong antiarteriosclerotic action due to its high affinity for vascular tissues and antioxidative action. It has also been reported that azelnidipine does not cause tachycardia associated with the baroreceptor reflex due to vasodilatation. In this study, the antiarteriosclerotic and cardiac hypertrophy-inhibitory effects, and the autonomic nervous activity in essential hypertension of azelnidipine were investigated. The study was performed using the following 2 protocols: 1) Pulse wave velocity (PWV), carotid arterial intima media thickness (IMT), echocardiography, high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), adiponectin, brain natriuretic peptide (BNP), and 8-isoprostane were measured after an initial treatment with azelnidipine. 2) The treatment was switched to azelnidipine in patients who had previously been under treatment with amlodipine for essential hypertension, and 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG), measurements of plasma norepinephrine, atrial natriuretic peptide (ANP), and BNP, Holter electrocardiography, and heart rate variability analysis were performed. PWV, IMT, hs-CRP, IL-6, and TNF-alpha significantly decreased. The levels of 8-isoprostane, an antioxidative marker, were also significantly decreased, while adioponectin levels were significantly increased after the initial treatment with azelnidipine. After switching from amlodipine, azelnidipine exhibited a hypotensive effects comparable to amlodipine, and significantly decreased heart rate and the total number of extrasystoles. Noradrenaline levels and the LF/HF ratio were significantly decreased, and the washout rate was significantly reduced on 123I-MIBG myocardial scintigraphy. These findings suggest that azelnidipine inhibits the enhancement of sympathetic nervous activity and the progression of arteriosclerosis through its antioxidative effects. Topics: 3-Iodobenzylguanidine; Adipokines; Aged; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Autonomic Nervous System; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiomegaly; Carotid Arteries; Catecholamines; Cytokines; Dihydropyridines; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Pulse; Radionuclide Imaging; Radiopharmaceuticals | 2007 |
[Also for problem cases; successful first line therapy].
Topics: Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Treatment Outcome | 2005 |
Unique atheroprotective property of azelnidipine, a dihydropyridine-based calcium antagonist.
Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic synd Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Azetidinecarboxylic Acid; Biomarkers; Calcium; Cardiovascular Diseases; Cells, Cultured; Chemokine CCL2; Diabetes Mellitus; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Insulin Resistance; Interleukin-8; Models, Biological; Reactive Oxygen Species; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Umbilical Veins | 2005 |
Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice.
Angiotensin II type 1 receptor blockers (ARB) are widely recognized to have a vasculoprotective effect. Accumulating data have revealed that calcium antagonists also retard atherosclerosis. We examined the possibility that combination therapy of ARB and calcium antagonists could more effectively prevent atherosclerosis than monotherapy.. We observed a marked increase in the atherosclerotic area, associated with the exaggerated expression of nicotinamide adenine dinucleotide (phosphate), reduced form [NAD(P)H] oxidase subunits (p22 and p47) and superoxide anion production, in the aorta of apolipoprotein E-deficient mice maintained on a 1.25% high-cholesterol diet for 10 weeks. A calcium antagonist, azelnidipine, at a dose of 1 mg/kg a day or an ARB, olmesartan, at a dose of 3 mg/kg a day, significantly inhibited these parameters, with no change in systolic blood pressure and the blood cholesterol level. Moreover, the co-administration of lower doses of azelnidipine (0.1 mg/kg a day) and olmesartan (1 mg/kg a day) significantly inhibited the atherosclerotic area and oxidative stress, whereas azelnidipine or olmesartan alone at these doses did not affect these parameters. Furthermore, we observed similar inhibitory effects of azelnidipine or olmesartan on angiotensin II-induced NADPH oxidase activity and Akt activity in cultured vascular smooth muscle cells.. These results suggest that the co-administration of calcium antagonists and ARB synergistically blunts oxidative stress at least partly through the inhibition of Akt activity and enhances the beneficial effects of these drugs on atherosclerosis compared with monotherapy. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apolipoproteins E; Arteriosclerosis; Azetidinecarboxylic Acid; Blotting, Western; Calcium Channel Blockers; Cells, Cultured; Dihydropyridines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Imidazoles; Mice; Mice, Knockout; Muscle, Smooth, Vascular; NADPH Oxidases; Olmesartan Medoxomil; Oxidative Stress; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Superoxides; Tetrazoles; Time Factors | 2005 |
Reduced progression of atherosclerosis in apolipoprotein E-deficient mice treated with lacidipine is associated with a decreased susceptibility of low-density lipoprotein to oxidation.
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 | 2004 |
[Intima-media thickness in hypertensive patients. Calcium blockers controls atherosclerosis].
Topics: Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Randomized Controlled Trials as Topic; Tunica Intima; Tunica Media | 2002 |
[Antihypertensive therapy. Can a calcium antagonist stop arteriosclerosis?].
Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension | 2001 |
[ELSA Studies studies progression of atherosclerosis. Calcium antagonist arrests the process more than a beta-blocker].
Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Humans; Hypertension; Randomized Controlled Trials as Topic | 2001 |
Immunochemical detection of a lipofuscin-like fluorophore derived from malondialdehyde and lysine.
The accumulation of fluorescent age pigment or lipofuscin is a frequently observed age-associated cellular alteration in a variety of postmitotic cells of many species. These pigments are observed within granules composed, in part, of damaged protein and lipid. Modification of various biomolecules by aldehyde products of lipid peroxidation is believed to contribute to lipofuscin and ceroid formation. In the present study, we raised a monoclonal antibody (MAb 1F83) directed to the malondialdehyde-modified protein and identified a lipofuscin-like dihydropyridine fluorophore as the major epitope. This antibody was used to conclusively demonstrate that the fluorophore forms on oxidatively modified low density lipoproteins. In addition, we demonstrated that the materials immunoreactive to MAb 1F83 indeed constituted the atherosclerotic lesions, in which intense positivity was associated primarily with macrophage-derived foam cells. The results of this study suggest that the reaction between the lipid peroxidation-derived aldehyde and primary amino groups of protein might represent a process common to the formation of the lipofuscin-like fluorophore during aging and its related diseases. Topics: Animals; Antibodies, Monoclonal; Arteriosclerosis; Copper; Dihydropyridines; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fluorescent Dyes; Hemocyanins; Humans; Immunohistochemistry; Insulin; Lipid Peroxidation; Lipofuscin; Lipoproteins, LDL; Lysine; Malondialdehyde; Mice; Mice, Inbred BALB C; Oxidation-Reduction; Serum Albumin, Bovine | 2001 |
[Calcium antagonists lower not only blood pressure. Arteriosclerosis is braked too].
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 | 2001 |
Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol-fed hamsters.
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 | 2000 |
The calcium-channel blocker lacidipine reduces the development of atherosclerotic lesions in the apoE-deficient mouse.
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 | 2000 |
Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.
Angiotensin II activates NAD(P)H-dependent oxidases via AT1-receptor stimulation, the most important vascular source of superoxide (O2*-). The AT1 receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O2*- production and whether AT1-receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction.. Vascular responses were determined by isometric tension studies, and relative rates of vascular O2*- production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT1-receptor mRNA was quantified by Northern analysis, and AT1-receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O2*- production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O2*- production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT1-receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O2*- and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT1 receptor mRNA was upregulated to 166+/-11%, accompanied by a comparable increase in AT1-receptor density.. Hypercholesterolemia is associated with AT1-receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O2*- production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT1-receptor antagonist suggests a crucial role of angiotensin II-mediated O2*- production in the early stage of atherosclerosis. Topics: Acetylcholine; Acridines; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteriosclerosis; Diet, Atherogenic; Dihydropyridines; Electron Spin Resonance Spectroscopy; Hypercholesterolemia; Lipids; Luminescent Measurements; Macrophages; Male; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Phenylephrine; Rabbits; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, LDL; Renin-Angiotensin System; Superoxides; Tetrazoles; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents | 1999 |
Possible mechanism for the anti-atherosclerotic action of the calcium channel blocker AE0047 in cholesterol-fed rabbits.
1. The present study was designed to investigate the anti-atherosclerotic effect of AE0047, a calcium channel blocker, and to compare it with that of nilvadipine in cholesterol-fed rabbits. Furthermore, the effects of AE0047 on low-density lipoprotein (LDL) oxidation were studied in vitro. 2. A 7 week treatment period with AE0047 (3 and 10 mg/kg, p.o.) led to a dose-dependent reduction in the lipid deposition area by Oil Red-O staining (surface index) without affecting serum lipid levels. There was no reduction in the surface index following treatment with the same dose of nilvadipine (10 mg/kg). 3. In a vehicle-administered high-fat diet group of rabbits, levels of total cholesterol (TC) and esterified cholesterol (EC) and calcium content in the aorta were increased approximately two- to three-fold over those of the normal diet group. Increased levels of TC and EC and calcium content were reduced to the same levels as the normal diet group by AE0047 treatment, whereas nilvadipine did not affect TC and EC levels. 4. In an in vitro study, AE0047 (10 micromol/L) inhibited LDL oxidation and the aggregation of apolipoprotein (Apo) B-100 induced by Cu2+. Furthermore, AE0047 inhibited the degradation of oxidized LDL by macrophages. In contrast, the same dose of nilvadipine (10 micromol/L) did not inhibit either LDL oxidation or the aggregation of ApoB-100. 5. In summary, AE0047 inhibited LDL oxidation, resulting in a decrease of its uptake into macrophages and an inhibition of cholesterol esterification. This leads to an anti-atherosclerotic effect of AE0047. Thus, AE0047 may have therapeutic potential in preventing cardiovascular disease in hypertensive patients. Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Body Weight; Calcium; Calcium Channel Blockers; Cholesterol, Dietary; Diet; Diet, Atherogenic; Dihydropyridines; Lipids; Lipoproteins, LDL; Male; Oxidation-Reduction; Rabbits | 1998 |
The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved?
Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm, at least in vitro, the pharmacological potential of the compound to influence negatively the process of atherogenesis. Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Brain; Calcium Channel Blockers; Cell Division; Dihydropyridines; In Vitro Techniques; Male; Membranes; Muscle, Smooth, Vascular; Nitrendipine; Rats; Rats, Sprague-Dawley; Stereoisomerism | 1998 |
Effect of lercanidipine and its (R)-enantiomer on atherosclerotic lesions induced in hypercholesterolemic rabbits.
The in vivo antiatherogenic activity of the calcium antagonist lercanidipine and its (R)-enantiomer was investigated in two different types of atherosclerotic lesions (hyperplastic and fatty-streak lesions) in rabbits. Lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) as well as its (R)-enantiomer at 3 mg kg(-1) week(-1) were given by subcutaneous injection for 10 weeks to White New Zealand rabbits, with cholesterol feeding beginning at week 2. The hyperplastic lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty streak lesions were induced by cholesterol feeding. In untreated animals (n=5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries without collar showed a intima/media (I/M) ratio of 0.03+/-0.02, whereas in carotids with a collar the ratio was 2+/-0.42. In lercanidipine-treated animals a significant and dose-dependent effect on intimal hyperplasia was observed. I/M ratios were 0.73+/-0.4, 0.42+/-0.1, 0.32+/-0.1 for 0.3, 1, and 3 mg kg(-1) week(-1), respectively (P<0.05). The lercanidipine enantiomer (3 mg kg(-1) week(-1)) was as effective as the racemate (0.41+/-0.11). Proliferation of smooth muscle cells, assessed by incorporation of BrdU into DNA, was reduced by about 50%, 70%, 85%, and 80% by lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) and its (R)-enantiomer, respectively. The area of fatty-streaks in the aorta (n = 11-15) was significantly reduced by lercanidipine (3 mg kg(-1) week(-1), 16% vs 27%, P<0.05), a trend was observed also with lower doses. When different segments of the aorta were considered (arch, thoracic, abdominal) a significant and dose-dependent effect in the thoracic and abdominal aorta was observed also at lower doses. The (R)-enantiomer was as effective as lercanidipine. These results suggest a direct antiatherosclerotic effect of lercanidipine, independent of modulation of risk factors such as hypercholesterolemia and/or hypertension as demonstrated by the absence of stereoselectivity. Topics: Animals; Arteries; Arteriosclerosis; Calcium Channel Blockers; Cholesterol, Dietary; Dihydropyridines; Disease Models, Animal; Hypercholesterolemia; Hyperplasia; Macrophages; Male; Rabbits | 1998 |
Oxidized low-density lipoprotein increases the production of intracellular reactive oxygen species in endothelial cells: inhibitory effect of lacidipine.
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 | 1998 |
Action of elgodipine on atherosclerosis development, cell growth, and oncogene expression in vascular smooth muscle cells.
1. Elgodipine (ELG) had no significant effect on aortic content of cholesterol, plasma cholesterol, or triglycerides concentrations in cholesterol-fed rabbits. However, ELG administration produced a dose-dependent and significant reduction of calcium content of the aorta. 2. In vitro studies showed that ELG was able to inhibit vascular smooth muscle proliferation through a mechanism independent of the expression of the transcription factors c-fos and c-jun. Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Blood Pressure; Calcium; Calcium Channel Blockers; Cell Division; Cells, Cultured; Cholesterol, Dietary; Dihydropyridines; Gene Expression; Hypercholesterolemia; Lipoproteins; Male; Muscle, Smooth, Vascular; Proto-Oncogene Proteins; Rabbits; Triglycerides | 1997 |
Direct antiatherogenic activity of isradipine and lacidipine on neointimal lesions induced by perivascular manipulation in rabbits.
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 | 1997 |
Effect of lacidipine on fatty and proliferative lesions induced in hypercholesterolaemic 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 | 1996 |
Calcium channel blockers. Lessons learned from MIDAS and other clinical trials.
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Dihydropyridines; Humans; Hypertension | 1996 |
Data collection and statistical analyses in ELSA. European Lacidipine Study on Atherosclerosis.
Topics: Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Multicenter Studies as Topic; Statistics as Topic | 1996 |
[Effect of efonidipine hydrochloride (NZ-105) on modification of low density lipoprotein induced by rat cultured endothelial cells].
We studied the effects of efonidipine hydrochloride [NZ-105: (+/-)-2-[benzyl (phenyl) amino] ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2- yl)-4-(3-nitro-phenyl)-3-pyridinecarboxylate hydrochloride ethanol] and nisoldipine on endothelial cell-induced low density lipoprotein (LDL) modification. The modification of LDL by cultured rat endothelial cells was performed by incubating 3 micrograms protein/well LDL with 5 microM CuSO4 for 24 hr at 37 degrees C in the presence of confluent cells. The extent of modification was assayed by measuring the thiobarbituric acid-reactive substances (TBARS). Efonidipine hydrochloride reduced the TBARS level in a dose-dependent manner. At 3 x 10(-7) M, efonidipine hydrochloride showed a significant effect. On the other hand, the significant effect of nisoldipine was observed only at 10(-5) M. Thus the action of efonidipine hydrochloride on the inhibition of LDL-modification was much more potent than that of nisoldipine. As the modification of LDL was thought to play a key role in the initiation and progression of atherosclerosis, efonidipine hydrochloride may be useful against atherosclerosis. Topics: Animals; Arteriosclerosis; Calcium Channel Blockers; Cells, Cultured; Depression, Chemical; Dihydropyridines; Dose-Response Relationship, Drug; Endothelium; Lipoproteins, LDL; Male; Nisoldipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Wistar | 1995 |
Effect of lacidipine on the carotid intimal hyperplasia induced by cuff injury.
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 | 1994 |
[Effect of efonidipine hydrochloride (NZ-105), a new dihydropyridine calcium antagonist, on the experimental atherosclerosis in cholesterol-fed rabbits].
We studied the effect of efonidipine hydrochloride [NZ-105:(+-)-2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl )-3-pyridine-carboxylate hydrochloride ethanol], a newly synthesized dihydropyridine calcium antagonist, on atherosclerosis in 1% cholesterol-fed rabbits. NZ-105 (10, 30 and 100 mg/kg) was orally administered to the animals twice a day for 10 weeks. NZ-105 did not cause any significant change in the plasma lipid levels. The area of atherosclerotic lesion was reduced by 37% (P < 0.05) in the aortic arch and by 54% (P > 0.05) in the thoracic aorta of rabbits administrated 100 mg/kg of NZ-105. The content of cholesterol ester in the aorta was also reduced by 64% (P < 0.05) in the aortic arch and by 73% (P > 0.05) in the thoracic aorta. These results suggest that NZ-105 may suppress the development of atherosclerosis without affecting the plasma lipids. Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Calcium; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Dihydropyridines; Lipids; Nitrophenols; Organophosphorus Compounds; Rabbits | 1994 |
Calcium channel antagonists. What do the second-generation agents have to offer?
Calcium channel antagonists have gained widespread acceptance for treatment of a variety of cardiovascular disorders. Newer drugs of the dihydropyridine class are especially attractive for treating hypertension and angina because of their increased vascular selectivity, favorable side-effect profile, and pharmacokinetics that allow once-daily dosing. In the future, calcium channel antagonists may also play a role in antiatherogenic therapy and in treatment of congestive heart failure and cerebrovascular disease as results of prospective studies become available and new agents are developed. Topics: Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Cerebrovascular Disorders; Dihydropyridines; Diltiazem; Heart Failure; Humans; Verapamil | 1994 |
Cardiovascular profile of MPC-1304, a novel dihydropyridine calcium antagonist: comparison with other calcium antagonists.
The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris. Topics: Animals; Arteriosclerosis; Atrioventricular Node; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular System; Coronary Circulation; Dihydropyridines; Dogs; Electric Stimulation; Female; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; Rabbits | 1993 |
The antiatherosclerotic effect of the calcium antagonists and their implications in hypertension.
Calcium-dependent processes involved in atherosclerotic lesion formation include platelet aggregation, monocyte adhesion, release of growth factors, cell proliferation and migration, protein and collagen secretion and synthesis, and endothelial necrosis. In addition, the calcium (Ca2+) component of smooth muscle cell contraction contributes to one of the main risk factors, hypertension. The ability of the calcium channel blockers (CCBs) to interrupt the sequence of events that culminates in the formation of atherosclerotic lesions has been demonstrated in animal models and clinical trials. These studies have involved the short-acting CCBs. The results of this animal study show that manidipine, a new long-acting CCB, produces a dose-dependent reduction in atherosclerotic lesion formation without reducing plasma cholesterol. Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cholesterol; Cholesterol, Dietary; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Male; Nitrobenzenes; Piperazines; Rabbits | 1993 |
Effects of lacidipine on experimental models of atherosclerosis.
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 | 1993 |
Manidipine inhibits the progression of hypertension and atherosclerosis in endothelium-injured and cholesterol-fed Goldblatt 2K1C rats.
In the present study, arteriosclerotic change of the aorta was induced in rats. The effects of manidipine hydrochloride on the resulting hypertension and arteriosclerotic change were studied. In endothelium-injured cholesterol-fed Goldblatt 2K1C rats, moderate elevation of blood pressure was noted at 3, 4, and 5 weeks. Laboratory studies performed at the end of 6 weeks also showed hypercholesterolemia, accompanied by a reduction of triglycerides and HDL cholesterol. Regular doses of manidipine (200 or 500 mg/kg) resulted in a dose dependent inhibition of the blood pressure elevation and a reduction of HDL cholesterol, but had no effect on cholesterol or triglyceride levels. Morphological studies in endothelium-injured rats afflicted with hypercholesterolemia and hypertension, showed medial thickening and intimal hyperplasia. Hyperplasia of the intima was a result of excessive proliferation of the smooth muscle cells. These cells showed an unusually large number of fat droplets and were considered indicative of atheromatous plaque formation. In rats treated with manidipine, hyperplasia of the media was completely suppressed while hyperplasia of the intima was reduced by a minimum of 50%. This study demonstrated that hypercholesterolemia and hypertension produced arteriosclerotic change in endothelium-injured rats, which was inhibited by manidipine. It is not known whether antiarteriosclerotic action was involved in the antihypertensive effect of manidipine. Topics: Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Endothelium, Vascular; Heart Rate; Hypertension, Renovascular; Male; Nitrobenzenes; Piperazines; Rats; Rats, Wistar | 1992 |
Concomitant aspirin treatment abolishes the antiatherosclerotic effects of the calcium channel blocker isradipine mediated by PGI2.
108 male rabbits, aged 6 months, with experimental hypercholesterolemia and experimental abdominal aortic lesioning received different regimen of antiatherosclerotic treatment; 36 of them were treated with isradipine, a dihydropyridine calcium antagonist (0.3 mg/kg/daily), 36 with isradipine in combination with aspirin whereas 36 animals received placebo. The entry of 125I-radiolabelled LDL into the aorta was demonstrated to be significantly diminished in isradipine-treated rabbits as well as positive Sudan-III-staining and aortic cholesterol content were in comparison to placebo. This benefit was almost completely abolished by concomitant aspirin-treatment. The notable increase in vascular prostacyclin (PGI2) is supposed to mediate the strong antiatherosclerotic effect of isradipine resulting in an inhibition of LDL-entry and vascular cholesterol accumulation. Aspirin almost totally blocked the raise in PGI2-synthesis by the inhibition of cyclooxygenase detected in isradipine-treated animals. It can be concluded, that aspirin-treatment may minimize the antiatherosclerotic actions of calcium antagonists which are mediated by the PG-system. Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Aspirin; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Epoprostenol; Humans; Hypercholesterolemia; Isradipine; Kinetics; Lipid Metabolism; Lipoproteins, LDL; Male; Rabbits | 1992 |
The diminished extracellular matrix production induced by isradipine, a calcium channel blocker, is completely abolished by cyclooxygenase inhibition.
Collagen and glycosaminoglycan synthesis are well known to be enhanced during early atherogenesis. In this experimental study the synthesis of collagen was determined using 14C proline incorporation, the glycosaminoglycan production by means of 35S-sulphate incorporation and subsequent quantification by means of autoradiography. Isradipine, a new calcium channel blocker of the dihydropyridine family at a dose of 0.3 mg/kg significantly (p less than 0.01) decreased the incorporation of both the radioactive precursors. This effect was abolished by a concomitant aspirin treatment, while aspirin alone did not exert any significant effect on the precursor incorporation. These data suggest that isradipine, which is known to stimulate PGI2 synthesis, may exert this antiatherosclerotic inhibitory action on extracellular matrix production via the endogenous liberation of PGI2. Topics: Animals; Arteriosclerosis; Aspirin; Calcium Channel Blockers; Collagen; Cyclooxygenase Inhibitors; Dihydropyridines; Drug Interactions; Epoprostenol; Extracellular Matrix; Glycosaminoglycans; Isradipine; Male; Rabbits | 1992 |
Experimental antiarteriosclerotic effects of calcium antagonists.
Topics: Adult; Aged; Aged, 80 and over; Animals; Arteries; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cell Wall; Dihydropyridines; Humans; Microscopy, Electron; Middle Aged; Rats; Rats, Inbred SHR | 1990 |
Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile.
The effects of a new 1,4-dihydropyridine derivative amlodipine have been compared with results from our previous work. Application of amlodipine at a concentration of 1.6 X 10(-6) M to isolated guinea-pig papillary muscle for 120 minutes produced a 50% reduction in tension development compared with a concentration of 3.7 X 10(-7) M nifedipine needed to produce the same result under identical conditions. This suggests that amlodipine has even weaker negative inotropic effects than nifedipine. In isolated porcine coronary strips, the K+-induced contractions were approximately 10,000 times more sensitive to the relaxing effects of nisoldipine, nitrendipine and nicardipine than to those of papaverine, whereas nifedipine and amlodipine were 3,000 times more potent than papaverine. However, in comparison with these in vitro actions, the efficacy of amlodipine appears to be greater in vivo: Simultaneous subcutaneous injection of nifedipine (20 mg/kg) and of equimolar doses of nisoldipine and felodipine attenuated the myocardial calcium uptake by rat hearts in situ (stimulated with a single subcutaneous dose of 30 mg/kg isoproterenol) with the same efficacy, whereas the actions of nitrendipine and nimodipine were considerably weaker. In contrast, amlodipine antagonized isoproterenol-stimulated myocardial calcium accumulation more effectively. Furthermore, amlodipine exhibited a high antihypertensive potency combined with rapid onset and long duration of action: Amlodipine (10 mg/kg orally [p.o.]) reduced the blood pressure of spontaneously hypertensive rats almost to the same extent as nifedipine, nitrendipine, verapamil and felodipine administered at the much higher doses of 100 mg/kg p.o. Amlodipine (20 mg/kg/day p.o.) maintained normal blood pressure during the whole life span of Dahl-S rats (5 months), but this dose is considerably lower than that reported for other 1,4-dihydropyridines. The survival of NaCl-loaded Dahl-S rats increased from 20 to 100% after administration of amlodipine (20 mg/kg/day p.o.) over 10 weeks: The effective dose of other calcium antagonists is approximately 5 times higher, but well tolerated as, e.g., demonstrated in long-term studies on Dahl-S rats with nitrendipine over 12 months. Increases in systemic arteriolar tone can be visualized in the ocular fundus of spontaneously hypertensive rats. After amlodipine (10 mg/kg p.o.) arteriolar spasm declines. Prophylaxis with 2 doses of 20 mg/kg amlodipine daily in NaCl-loaded Dahl-S rats Topics: Amlodipine; Animals; Antihypertensive Agents; Arteriosclerosis; Calcium; Calcium Channel Blockers; Dihydropyridines; Heart; In Vitro Techniques; Isoproterenol; Mesenteric Arteries; Muscle, Smooth, Vascular; Myocardium; Nifedipine; Rabbits; Rats; Retinal Artery; Swine; Vasoconstriction | 1989 |