Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal experiments have shown that the administration of calcium antagonists can prevent or slow the progression of atherosclerosis by inhibiting calcium overload and interfering with lipid metabolism and deposition. These encouraging results have prompted clinical trials to evaluate the effects of calcium antagonists (dihydropyridines and diphenylalkylamines) on atherosclerotic plaque formation. In patients with coronary heart disease, several studies have already shown that calcium antagonists can have a positive effect on plaque evolution, while in hypertensive patients no such study has been published to date. The Verapamil in Hypertension Atherosclerosis Study is an ongoing multicentre randomised double-blind parallel group trial comparing the antihypertensive efficacy of verapamil SR 240 mg/day with that of chlorthalidone 25 mg/day in 1464 patients with essential hypertension aged 40 to 65 years. In a randomised subgroup of patients (n = 550), who will be followed up for 3 years, B-mode ultrasonography is being employed to evaluate the effects of the 2 drugs on carotid wall thickness and carotid plaque development. Ultrasonographic evaluations are performed at baseline, after 3 months, and 1, 2 and 3 years after a standardised protocol to determine intimal-medial thickness in 4 segments of the extracranial carotid tree. The most interesting result to date is the high incidence of carotid alterations, with plaques present in 35% and arterial wall thickening in 31.8% of the 311 asymptomatic hypertensive patients processed so far. A preliminary evaluation of the antihypertensive efficacy of the trial medications after 6 months of double-blind treatment indicates a 63.5% response rate to monotherapy and a 7.8% drop-out rate because of drug inefficacy or intolerance.
 ...
PMID:Preliminary clinical experience with calcium antagonists in atherosclerosis. Verapamil in Hypertension Atherosclerosis Study Investigators. 128 76

Whether or not some classes of antihypertensive drugs have an anti-atherogenic action independent of the antihypertensive one has been investigated through a large series of experimental studies, primarily involving calcium antagonists. Most experimental investigations have shown a significant anti-atherogenic action of calcium antagonists, but only when the drug is administered simultaneously with the atherogenic stimulus (mainly cholesterol feeding). When the drug is administered weeks or months after the beginning of the atherosclerotic process (as in the Watanabe heritable hyperlipidemic rabbit), with a single exception, no antiatherogenic effect has been shown. The few clinical studies completed so far have been on symptomatic coronary patients. Little is known of the effects of calcium antagonists on asymptomatic lesions in the carotid arteries of hypertensive patients, in whom carotid plaques can be identified and followed-up by non-invasive ultrasound techniques. However, two such trials are underway. The Verapamil in Hypertension Atherosclerosis Study (VHAS) is an ongoing randomized trial, comparing the antihypertensive efficacy of verapamil 240 mg SR with chlorthalidone 25 mg in 1,464 essential hypertensives aged 40-65 years. In a random subgroup of patients (500), who will be followed for three years, B-mode ultrasonography is being carried out blindly to evaluate the effect of the two drugs on carotid wall thickness and on carotid plaques, when present. Preliminary baseline data are available in 440 of the hypertensive patients in whom ultrasound investigation was performed. The mean (+/- SD) age of these patients was 53.7 +/- 6.9 years; 32.5% had echocardiographically normal carotid walls; 30.9% showed intima-media thickening; and 36.6% had one or more plaques.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Atherosclerosis and calcium antagonists: the VHAS. The Verapamil-Hypertension Atherosclerosis Study (VHAS) Investigators. 128 14

Epidemiological studies indicate that there are biological interrelationships between blood pressure and blood lipids that may influence the mechanisms whereby hypertension is associated with an increased risk of coronary artery disease. Serotonin (5-HT) and thromboxane A2, which are released from aggregating platelets, mediate platelet-induced vasoconstriction, which itself significantly contributes to coronary artery constriction in vivo. Platelet aggregatory response to serotonin is modulated by disparate effects of lipoprotein fractions. This corresponds to the recognized differences in degree of atherogenicity of low- (LDL) and high-density lipoprotein (HDL). Amplification of serotonin-induced platelet aggregation by LDL and its inhibition by HDL support the hypothesis that 5-HT-mediated effects represent a mechanism clinically relevant to both chronic progression of atherosclerosis (particularly at sites of vascular injury and atherosclerotic plaques) and acute thrombotic events. Calcium antagonists differ in their platelet-inhibition potency, including their effects on platelet response to 5-HT and LDL. Verapamil and isradipine inhibit platelet aggregation induced by 5-HT at therapeutic concentrations. Isradipine also inhibits the amplifying effect of LDL on 5-HT-induced aggregation. These platelet effects of calcium antagonists appear to be neither group- nor class-specific but, rather, drug-specific.
 ...
PMID:Platelet activation by low-density lipoprotein and serotonin: effects of calcium antagonists. 137 30

Recent multicentre studies evaluating the therapeutic value of calcium antagonists in reducing the incidence of cardiovascular complications after myocardial infarction (secondary prevention) and in retarding the development of atherosclerosis in coronary artery disease (tertiary protection) are reviewed. The prognosis of patients after acute myocardial infarction can be improved not only by interventional measures such as aortocoronary bypass surgery or percutaneous transluminal catheter angioplasty, but also by various drugs. Numerous studies have shown that beta-blockers and platelet aggregation inhibitors can reduce mortality and reinfarction rates. Calcium antagonists in secondary prevention trials after acute myocardial infarction, however, have produced variable results. Whereas the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT) [Israeli SPRINT Study Group 1988] with nifedipine showed no beneficial effect of the drug, studies with verapamil in the Danish Verapamil Infarction Trial II (DAVIT II) [Danish Study Group on Verapamil in Myocardial Infarction 1990] and diltiazem in the Multicentre Diltiazem Postinfarction Trial (MDPIT) [Multicenter Diltiazem Postinfarction Trial Research Group 1988] as secondary prevention have demonstrated improvements in survival and cardiovascular complications, but these improvements were restricted to patients without heart failure. In view of the ability of calcium antagonists to reduce atheroma progression in coronary artery disease in animal models, the antiatherosclerotic effects of these agents in clinical studies have generally been disappointing. In the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) [Lichtlen et al. 1990], however, nifedipine treatment was associated with a 28% reduction in new lesion development, but did not affect the development of severe lesions. Similar results have been obtained with nicardipine.
 ...
PMID:Secondary and tertiary prevention with calcium antagonists in coronary artery disease. 137 87

The adherence of monocytes to the arterial endothelium followed by its migration into the arterial intima is the earliest event in atherogenesis. The vasoconstrictive peptide, Endothelin-1 (ET-1), is elevated in patients with atherosclerosis. We were interested to know whether ET-1 was a chemoattractant for blood monocytes. Using the modified membrane filter technique for chemotaxsis assessment, ET-1 increased monocyte chemotaxis in a dose-dependent manner. Ca2+ channel blockers, Nifedipine, Diltiazem and Verapamil (5 microM), reduced ET-1 chemotaxsis more than 60% (P < 0.001). Aspirin and Indomethacin (1 mM and 100 microM, respectively) reduced migration by 23% (P < 0.05). Alpha-Lipoic acid, Probucol and Neomycin (100 microM) were also migration inhibitory (37%, P < 0.01). These results suggest that ET-1 is a strong chemoattractant for blood monocytes; Ca2+ influx is probably the major stimulus for the accelerated migration induced by ET-1.
 ...
PMID:Chemotaxis of human blood monocytes toward endothelin-1 and the influence of calcium channel blockers. 147 72

The main objective of the study was to investigate the effect of the calcium antagonists Verapamil (2 mg.kg-1.day) and Nifedipine (1 mg.kg-1.day-1) on cholesterol (1%) induced atherosclerosis in rabbits. The drugs were administered s.c. twice daily over a period of 8 weeks. Blood lipid levels were determined three times during the experiment. After the experimental period the animals were killed and macroscopic changes on the aorta were recorded. For histochemical investigation samples were taken from the arch of the aorta and coronary artery. In cryostat sections lipids were determined by Sudan black B and Fett rot 7 B and the following enzymes were assayed: acid phosphatase, non-specific and acid esterase, acid beta-galactosidase, dipeptidyl peptidase I and II, and glucose-6-phosphate dehydrogenase. Following treatment with the calcium antagonists the levels of triacylglycerols and of total cholesterol were significantly increased in comparison with the control and diet groups. The ratio of HDL cholesterol to total cholesterol decreased in the treated animals. In lipoid plaques the activity of enzymes was enhanced in all experimental animals. There were however no qualitative differences in the composition of plaques between individual groups, which exhibited only quantitative differences. The number of migrating macrophages was increased only in the nifedipine treated animals. The extent of plaques was significantly decreased after nifedipine treatment, whereas verapamil failed to exert antiatherogenic effect. (Tab. 2, Fig. 4, Ref. 22.).
 ...
PMID:[The effect of verapamil and nifedipine on the development of experimental atherosclerosis in rabbits]. 152 79

Elevation of cytosolic ionized calcium plays a critical role in human platelet activation. We have evaluated three well-characterized calcium antagonists for their ability to prevent thrombin-induced calcium mobilization in Fura 2 AM-loaded platelets and also their ability to inhibit platelet-vessel wall interactions. Thrombin (0.2 U/ml) caused significant elevation of cytosolic calcium (basal 84 +/- 18, activated 546 +/- 76 nM; n = 3). Verapamil, diltiazem, and nifedipine (100 microM) did not exert any inhibitory effect on thrombin-mediated calcium elevation. Untreated platelets perfused through a Baumgartner chamber containing a rabbit aorta preparation reacted with exposed and denuded subendothelium. The percentage of the total area covered by control platelet thrombi was 39.6 +/- 3.4. Diltiazem and Nifedipine significantly reduced the percentage of area covered by platelet thrombi, but the drugs were not as effective as aspirin (8.2 +/- 1.4). Calcium antagonists studied did not inhibit thrombin-stimulated elevation of cytosolic calcium in blood platelets. Although these drugs have been shown to prevent in vitro platelet aggregation and offer some protection against risks for atherosclerosis and thrombosis, they failed to significantly inhibit platelet-vessel wall interactions leading to formation of spread platelets and aggregates.
 ...
PMID:Influence of calcium antagonists on thrombin-induced calcium mobilization and platelet-vessel wall interactions. 162 53

The objective of the work was to follow up on a model of experimental atherosclerosis induced in rabbits by a 1% cholesterol diet the mutual relationship of the deposition of total cholesterol as well as esterified and free fatty acids in the liver and the formation of lipid plaques in the rabbit aorta. The authors investigated also the influence exerted on this process by the s.c. administration of calcium antagonists--Verapamil 0.25 mg.kg-1.day-1 (Lek Ljubl., Jugoslavia), Dilthiazem 2 mg.kg-1.day-1 (Lachema CSFR) and Isradipine 2.5 mg.kg-1.day-1 (Isradipine--N Sandoz, Ltd, Switzerland). The interference of calcium antagonists with the lipid metabolism in the liver as well as the transport mechanism of lipids in the blood stream is differentiated. Verapamil administered in therapeutic doses promotes HDL-cholesterol formation and thus hastens the cholesterol transport from the blood stream into the liver where the latter cumulates. This may be one of the mechanisms of the antiatherogenic action of verapamil. On the other hand, isradipine and in particular dilthiazem administered in treble doses, as compared with therapeutic doses, slightly potentiated the formation of lipid plaques in the rabbit aorta and reduced the HDL-cholesterol level and thus also the cholesterol shift to the liver.
 ...
PMID:[Relation between hepatic lipid metabolism and the formation of lipid plaques in the rabbit aorta in an experimental model of atherosclerosis]. 176 18

Calcium ions act as intracellular messengers in numerous cellular functions and participate also in the development of the atherosclerotic process. Calcium homeostasis could be an important factor in the development of atherosclerosis. One of the drugs which interferes with calcium homeostasis are calcium channel blockers. A number of studies have investigated the possibility whether these drugs may be also useful for prevention of atherosclerosis. However, other investigators have reported that calcium channel blockers did not suppress the atherosclerotic process. In our work we assumed the direct influence of calcium channel blockers on transendothelial transport mechanisms. Therefore we decided to investigate the influence of verapamil, diltiazem and isradipine on the development of experimental atherosclerosis in rabbits. Verapamil administered twice daily, 0.125 mg per kg s. c., reduced the size of atheromatous plaques in the thoracic aorta and the level of total cholesterol and triglycerides in serum. This above effect was not present after administration of diltiazem in doses of 1.0 mg per kg and isradipine 1.25 mg per kg twice daily subcutaneously. Our conclusion is that the anti-atherosclerotic effect of calcium channel blockers is dose-dependent. It is not clear whether this effect takes place in the plasma compartment and/or in the intracellular compartment.
 ...
PMID:[The effect of calcium channel blockers on experimental hypercholesteremia in rabbits. Biochemical and histochemical study]. 178 82

Calcium channel blockers may retard development and progression of coronary arteriosclerosis in man because of protective effects on membranes, (especially the endothelium), relaxation of vessel walls, inhibition of various platelet functions, impairment of proliferation and migration of smooth muscle cells in the vessel wall, and an improvement of vascular cholesterol metabolism. In animal trials development of atheromas in large arteries induced by cholesterol-rich food and other stimuli of atherogenesis could be successfully retarded by a broad variety of calcium channel blockers. Some clinical observations in patients with coronary artery disease pointed at positive effects of calcium antagonists in coronary arteriosclerosis. To date, the results of three prospective placebo-controlled trials with calcium antagonists in coronary arteriosclerosis are available. In all trials progression of atherosclerosis was assessed by serial angiograms: 1) INTACT (nifedipine: 20 mg four times daily; observation period: 3 years, two coronary angiograms); 2) Study of the Montreal Heart Institute (nicardipine: 30 mg three times daily; observation period: 2 years, two coronary angiograms); 3) FIPS (Frankfurt Isoptin Progression Study) (verapamil: 120 mg three times daily; observation period: 3 years, three coronary angiograms). Target variables in these studies were progression or regression of preexisting lesions, development of new lesions and the incidence of vessel occlusions. The INTACT and the Nicardipine studies preferably included patients in early stages of coronary artery disease. The patients of FIPS who were entered into the study immediately after coronary bypass surgery suffered from severe, advanced coronary artery disease. In the latter study progression of coronary artery disease was assessed separately in different vascular regions (bypassed and non-bypassed segments) and in the bypass grafts.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Modification of coronary arteriosclerosis in man by calcium antagonists?]. 179 51


1 2 3 4 Next >>