Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of BQ-485, a selective endothelin (ET)-A receptor antagonist, on the vasomotion induced by a low dose of ET were investigated. In the isolated rat heart perfused with Krebs-Henseleit solution at a constant flow, intracoronary bolus injection of ET-1 or ET-3 (10 pmol) elicited a rapid transient decrease, followed by a slight sustained increase, in the coronary perfusion pressure (CPP). The decrease in CPP induced by ET-1 was similar in magnitude to (approximately 30%) but shorter in duration than that induced by ET-3. Pretreatment of the heart with saponin (30 micrograms/ml) to denude the coronary endothelium abolished the decrease and markedly enhanced the increase in CPP induced by ETs, indicating that the vasorelaxing action of ETs is endothelium-dependent. The selective ETA receptor antagonist BQ-485 (1 microM) significantly prolonged the duration of the ET-1-induced decrease in CPP, made the vasodilatation by ET-1 indistinguishable from that by ET-3, and eliminated the subsequent increase in CPP. In the saponin-treated heart, BQ-485 also eliminated the ET-1-mediated increase in CPP. These findings suggest that, in rat coronary vascular beds, a low dose of ET-1 elicits vasoconstriction and endothelium-dependent vasodilatation through the ETA receptor on the vascular smooth muscle and presumably the ETB receptor on the endothelium, respectively. Furthermore, it is expected that selective ETA receptor antagonists, including BQ-485, may be able to protect the heart against ET-1-induced coronary spasm in situations, such as hyperlipidemia or artherosclerosis, in which the release and/or function of endothelium-derived vasorelaxing substances is impaired.
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PMID:Effects of BQ-485, a selective ETA antagonist, on endothelin-mediated vasomotion in rat coronary vascular beds. 858 27

According to contemporary views, the endothelium is not only a barrier separating blood from surrounding tissues, but a dynamic, heterogeneous organ, which possesses many secretory, metabolic and immunologic functions. Endothelial cells produce mediators, which regulate blood flow, influence platelet adhesion and aggregation, coagulation and fibrinolysis and also immunological response. Endothelial dysfunction is defined as an imbalance between vascular relaxing and contracting factors, between procoagulant and anticoagulant mediators or growth-inhibiting and growth-promoting substances. The definition is often confined to dysfunction of the vessel wall tonus control. The endothelial dysfunction frequently proceeds structural changes in vessels, as e.g. atherosclerotic plaque formation, neointima formation and vessel wall remodelling. This dysfunction has been confirmed in systemic hypertension, atherosclerosis, cardiac syndrome X, heart failure, using various invasive and non-invasive techniques. There are pharmacologic and non-pharmacologic methods to modify endothelial functions. It is obligatory to reduce risk factors of atherosclerosis, which lead to endothelial cell damage, i.e. hypertension, hyperlipidemia, cigarette smoking, estrogen deficiency and elevated levels of homocysteine. The role of physical exercise, low-cholesterol diet, discontinuation of smoking is emphasised. Among drugs statins, angiotensin-converting enzyme inhibitors and hormone replacement therapy are considered particularly beneficial. The importance of angiotensin receptor antagonists, endothelin receptor antagonists, L-arginine, growth factors and calcium-channel blockers for the improvement of endothelial function is studied.
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PMID:[Vascular endothelium--function, disorders and clinical modification probes]. 1171 25

Epidemiological studies showed that hypercholesterolemia is associated with higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 wk after cholesterol feeding compared with that in normocholesterolemic rabbits. Simvastatin at a clinical therapeutic dose (1.2 mg x kg(-1) x day(-1)) significantly decreased left ventricular weight by 14% and left ventricular myocyte sizes by 14% as isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA as assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. The addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects in simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at a clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.
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PMID:Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits. 1548 36