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

Thromboxane A2 (TxA2) is the main arachidonic acid metabolite in human platelets and exhibits two major activities; stimulation of platelet function, including secretion of platelet-derived storage products, e.g., 5-HT, PDGF, and vasoconstriction. Platelet hyperreactivity is typical for advanced stages of atherosclerosis and is paralleled by elevated circulating thromboxane levels. This is the target for TX-antagonistic compounds. Three classes of selective compounds are available: inhibitors of thromboxane synthase, antagonists of thromboxane receptors, and mixed-type agents. Positive experimental data with all of these compounds are available. However, clinical experience is limited and, in general, not convincing. This review discusses possible reasons for that and suggests that, in particular, the use of combined-type agents as antithrombotics may be superior to acetyl-salicylic acid in several forms of ischemic cardiovascular diseases.
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PMID:[Thromboxane A2 and prevention of cardiovascular diseases]. 129 Feb 97

Cardiovascular disease is a major cause of death. There is evidence that this disease is predicted and its progression influenced by various factors (e.g. hyperlipidaemia). In this review, we consider aspects of platelet structure and function which may explain how this cell type contributes to the pathogenesis of vascular disease. The platelet also contains bioamines (serotonin, 5-HT; histamine) which are potent vasoactive substances. Studies involving patients with peripheral vascular disease (PVD) where abnormalities in platelet function (platelet aggregation and platelet shape change) and in bioamine status (vascular, platelet and plasma bioamine concentrations) are reviewed. We also discuss how platelet activation (in vitro) and plasma lipids influence intraplatelet bioamine status. Finally, we report in vitro evidence of the effect of two drugs prescribed to PVD patients: aspirin and naftidrofuryl. Aspirin is an ineffective inhibitor of 5-HT-induced whole blood platelet aggregation whereas naftidrofuryl is effective in the presence or absence of aspirin. By identifying and altering the factors which contribute to the pathogenesis of atherosclerosis we will be better equipped to prevent, reverse or retard this process.
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PMID:Serotonin, histamine and platelets in vascular disease with special reference to peripheral vascular disease. 134 86

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.
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PMID:Platelet activation by low-density lipoprotein and serotonin: effects of calcium antagonists. 137 30

Serotonin (5-hydroxytryptamine, 5HT) is believed to play a role in vasospasm and increased platelet aggregability that in turn could contribute to atherosclerosis. The present study was designed to evaluate a possible participation of serotonin in the development of vascular complications in diabetes mellitus. Whole blood and plasma serotonin, the platelet uptake and release of the amine and serotonin- induced platelet aggregation were studied in 32 patients with Type 2 diabetes. The patients were divided into three groups according to the presence and advancement of retinopathy. Mean levels of blood serotonin content were significantly lower in diabetic patients. The concentration of the amine in the plasma was markedly increased in diabetes. It was correlated with vascular changes of the retina. We established that platelets from diabetic patients took up less serotonin when compared to the control group. Concomitantly enhanced spontaneous release of 5HT from platelets was observed. The platelets of diabetic patients showed increased response to serotonin. There was a relation between serotonin-induced aggregation and the presence of retinopathy. These results suggest that serotonin may be involved in the pathogenesis of diabetic vasculopathy.
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PMID:Blood serotonergic mechanisms in type 2 (non-insulin-dependent) diabetes mellitus. 151 34

We have examined the action of endothelin on healthy and diseased human epicardial coronary arteries to assess its possible role in coronary vascular disorders such as vasospasm and atherosclerosis. Endothelin (10(-10) mol l-1-10(-7) mol l-1) produced dose-dependent contractions in both normal and diseased vessels. The level of constriction was significantly greatly in healthy vessels at 10(-8) mol l-1 endothelin. A greater response was recorded in smaller, more distal vessel segments, irrespective of the pathology of the tissue. Endothelium denudation of disease-free segments had no significant effect on the response to endothelin. In the presence of a threshold dose of endothelin (10(-9) mol l-1), there was no measurable increase in the tension generated by potassium chloride, the thromboxane-mimetic U46619, noradrenaline and histamine. However, the response to 5-HT showed a large increase in arteries from four patients (440-147%) but slight or no increase in arteries from another three patients. We conclude that the interaction with other vasoconstrictor substances is a possible mechanism whereby endothelin may be involved in coronary artery vasospasm. In addition, endothelin may also be involved in the regulation of vascular tone of the small vessels of the heart.
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PMID:Effect of endothelin on normal and diseased human coronary arteries. 158 46

Serotonin (5-HT) is one important mediator of the coronary vasospasm and occlusion associated with thrombosis and atherosclerosis. 5-HT concentration-dependently contracted both canine and porcine coronary artery rings in vitro. In the dog, 5-HT-induced contraction was not blocked by either LY53857 (1 microM) or ketanserin (1 microM), but was blocked by the nonselective 5-HT receptor antagonist 1-naphthylpiperazine (1-NP) (100 nM), indicating 5-HT receptor involvement. Unlike the dog, both LY53857 (1 microM) and ketanserin (30 nM) antagonized 5-HT-induced contraction in pig arteries. Dissociation constants for LY53857 and ketanserin in porcine arteries were compared with those in rat jugular vein, a tissue possessing a well characterized 5-HT2 receptor. Both LY53857 (3 nM) and ketanserin (3 nM) antagonized 5-HT-induced contraction in rat jugular vein; however, the affinities of LY53857 and ketanserin in the rat jugular vein were significantly higher than those in the pig coronary. The rank order contractile potency for 5-HT, (alpha Me-5-HT) and sumatriptan in porcine coronary artery was consistent with that established for a 5-HT2 receptor, whereas the rank order potency in canine coronary artery indicated non-5-HT2 receptor involvement. Sumatriptan, a 5-HT1D receptor-selective agonist, was equieffective to 5-HT in contracting the canine coronary artery, a response inhibited by 1-NP (100 nM). Sumatriptan failed to contract either the pig coronary or rat jugular vein. In summary, significant differences exist in the 5-HT receptors that mediate contraction between the canine and porcine coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the serotonin receptors that mediate smooth muscle contraction in canine and porcine coronary artery. 160 89

We have studied the relationship between the early morphological changes and arterial responsiveness to vasoactive agents in a new animal model that is proposed to mimic the events of early human atherosclerosis. Atheroma-like lesions were produced by positioning a hollow Silastic collar (referred to as a cuff) around the common carotid arteries of rabbits. Following a period of either 48 h or 1, 2, or 4 weeks after surgery, vessels from both cuffed and sham-operated animals were removed, and vascular reactivity to cumulative concentrations of agonists were studied in isolated rings in organ baths. The contralateral arteries were perfused and fixed, studied by light microscopy, and the degree of intimal thickening was quantified by computer-assisted morphometric analysis and expressed as changes in the ratios of the cross-sectional areas of the intima and media in each artery. At 48 h, rings prepared from cuffed arteries were sixfold more sensitive to the contractile effects of serotonin (5-HT) than the corresponding controls. Histologically, such vessels showed some perivascular inflammation but no other morphological abnormality. At 7 days, cuffed vessels were again sixfold more sensitive to 5-HT than controls, and showed a thickened intima with marked smooth muscle proliferation and some infiltration by monocytes. Intimal/medial cross-sectional area ratios remained elevated at 2 and 4 weeks, but the supersensitivity to 5-HT diminished by 2 weeks to threefold and was absent at 4 weeks. The augmented reactivity to 5-HT at 48 h was specific, in that it did not occur for the alpha-adrenoceptor agonist, phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Supersensitivity to vasoconstrictor action of serotonin precedes the development of atheroma-like lesions in the rabbit. 170 11

High plasma cholesterol levels and plasma lipid peroxidation are associated with atherosclerosis. The effect of excessive dietary tryptophan on plasma lipid peroxidation was studied in rats fed a diet containing soybean oil (control), as well as an atherogenic diet, containing coconut oil and cholesterol. Feeding the atherogenic diet resulted in a 5-fold increment in plasma cholesterol concentration with no significant effect of the tryptophan supplementation. The plasma obtained from the hypercholesterolemic rats exhibited a 67% increased lipid oxidation (measured as thiobarbituric acid reactive substances) in comparison to normocholesterolemic plasma. Dietary tryptophan supplementation increased plasma lipid peroxidation by 9 and 21% in the control and in the hypercholesterolemic animals, respectively. Similarly, the excessive dietary tryptophan enhanced macrophage cholesterol esterification rate by 40 and 38% following cell incubation with the plasma obtained from the control and from the hypercholesterolemic animals, respectively. Since tryptophan is the precursor of serotonin we have measured urine concentration of 5-hydroxyindoleacetic acid (5HIAA), the metabolite of serotonin, and found 22 and 118% elevation in 5HIAA in the tryptophan fed control and hypercholesterolemic rats, respectively. The direct effect of tryptophan and serotonin on in vitro lipid peroxidation was also studied. Low density lipoprotein (LDL) was peroxidized by incubation with copper ions in the presence of tryptophan or serotonin. Serotonin was shown to enhance LDL peroxidation whereas tryptophan had no effect on LDL peroxidation. We conclude that excessive dietary tryptophan may be atherogenic since it enhanced plasma lipid peroxidation in hypercholesterolemic rats and increased macrophage uptake of plasma cholesterol. These effects are probably associated with increased plasma concentration of serotonin following the consumption of a tryptophan supplemented diet.
Atherosclerosis 1991 May
PMID:Excessive dietary tryptophan enhances plasma lipid peroxidation in rats. 171 63

We have investigated the growth promoting activities of two potent vasoactive substances, serotonin and angiotensin II (AII), on cultured porcine aortic smooth muscle cells (ASMC), using a defined serum-free medium. Serotonin (30 nM to 30 microM) stimulated ASMC DNA synthesis both alone and in combination with platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). Serotonin-induced DNA synthesis was significantly inhibited by ketanserin (5-hydroxytryptamine-2 (5HT-2) receptor antagonist). AII (3-10 nM) failed to stimulate ASMC DNA synthesis directly, either alone or in combination with PDGF or EGF. Since both serotonin and AII were found to activate phosphatidylinositol turnover and are reported to mobilise intracellular calcium, it is apparent that these events alone are insufficient to stimulate ASMC mitogenesis.
Atherosclerosis 1991 Jun
PMID:Comparison of the mitogenic activity of angiotensin II and serotonin on porcine arterial smooth muscle cells. 189 86

1. In a new animal model which mimics the cellular events of early human atherosclerosis, atheroma-like lesions were produced by positioning a hollow silastic collar around the common carotid arteries of rabbits. The functional significance of these arterial lesions on blood flow responses to vasoactive agents was then studied in anaesthetized rabbits in vivo. 2. After 1 week of lesion development, resting blood flow was lower in atherosclerotic (cuffed) carotid arteries compared with the contralateral, sham-operated control arteries. 3. Intra-carotid injection of serotonin (0.01-1 microgram) produced dose-dependent increases in blood flow in control arteries, but produced either smaller increases or decreases in flow in cuffed arteries. Serotonin caused complete vasospasm (zero blood flow) in one of six rabbits. 4. Acetylcholine (0.0001-0.01 microgram, intra-carotid) produced smaller increases in blood flow in cuffed arteries compared with controls. 5. These data support the proposal that morphological and functional alterations in large arteries in the early stages of atherogenesis play an important role in determining blood flow in vivo. The increased vascular reactivity to serotonin which accompanies development of the lesions might contribute to vasospasm.
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PMID:Enhanced vasoconstriction by serotonin in rabbit carotid arteries with atheroma-like lesions in vivo. 206 81


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