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)

In addition to preserving the permselectivity of the vascular wall and providing an antithrombogenic surface, the vascular endothelium contributes importantly to the regulation of vasomotor tone. Indeed, the endothelium participates in the conversion of angiotensin I to angiotensin II; the enzymatic inactivation of several plasma constituents such as bradykinin, norepinephrine, serotonin, and ADP; and the synthesis and release of vasodilator substances such as prostacyclin and the recently discovered endothelium-derived relaxing factor (EDRF). The diffusible EDRF released from the endothelium is nitric oxide or a substance closely related to it such as nitrosothiol. The endothelium also synthesizes and releases vasoconstrictive factors, including products derived from arachidonic acid metabolism and the recently discovered peptide endothelin. An increasing body of evidence from experimental and clinical studies indicates that EDRF and endothelium-derived contracting factors play an important role in vascular physiology and pathology. It has become apparent that the balance of these factors may be a major determinant of systemic and regional hemodynamics. Moreover, through generally opposite effects on growth-related vascular changes, contracting factors such as endothelin and relaxing factors such as EDRF also may be important determinants of the vascular response to injury in various disease states such as atherosclerosis and hypertension. It is clear that the vascular endothelium is a complex and dynamic organ. Understanding endothelium function in normal physiology and disease states is of potential clinical importance and should be the focus of future investigation.
 ...
PMID:Role of endothelium-derived relaxing factor in regulation of vascular tone and remodeling. Update on humoral regulation of vascular tone. 204 72

Atherosclerosis impairs endothelium-dependent relaxation of large conduit arteries. Because coronary resistance vessels are spared from the development of overt atherosclerosis, endothelium-dependent responses were examined in these vascular segments. Malaysian cynomolgus monkeys (n = 6) were made atherosclerotic by being fed a 0.7% cholesterol diet for 18 months. Control monkeys (n = 6) were fed a standard diet. Coronary microvessels (122-220 microns) were studied in a pressurized (20 mm Hg), no-flow state using a video-imaging apparatus. Relaxations of microvessels, preconstricted with the thromboxane analogue U46619, were determined in response to acetylcholine, bradykinin, the calcium ionophore A23187, adenosine, and sodium nitroprusside. Microvascular relaxations to bradykinin and A23187 were reduced in atherosclerotic monkeys compared with controls, whereas acetylcholine produced additional contraction in atherosclerotic monkeys. Responses of preconstricted microvessels to adenosine and sodium nitroprusside were identical in atherosclerotic and control animals. Indomethacin did not alter responses in control or atherosclerotic animals. Histologic examination revealed neither intimal thickening nor plaque formation in microvessels of this size class despite marked changes in conduit arteries. Electron microscopy showed minor alterations of endothelial cell morphology in microvessels of atherosclerotic animals. In conclusion, long-term hypercholesterolemia markedly impairs endothelium-dependent vascular relaxation in the coronary microcirculation where overt atherosclerosis does not develop. These changes in endothelial cell function may significantly alter regulation of myocardial perfusion by neurohumoral stimuli.
 ...
PMID:Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic primates. 211 36

We review below published studies of endothelium-dependent vasodilation in vivo. Endothelium-dependent vasodilation has been demonstrated in conduit arteries in vivo and in the cerebral, coronary, mesenteric, and femoral vascular beds as well as in the microcirculation of the brain and the microcirculation of cremaster muscle. The available evidence, although not complete, strongly suggests that the endothelium-derived relaxing factor generated by acetylcholine in the cerebral microcirculation is a nitrosothiol. The endothelium-derived relaxing factor generated by bradykinin in this vascular bed is an oxygen radical generated in association with enhanced arachidonate metabolism via cyclooxygenase. In the microcirculation of skeletal muscle, on the other hand, the vasodilation from bradykinin is mediated partly by prostacyclin and partly by an endothelium-derived relaxing factor similar to that generated by acetylcholine. Basal secretion of endothelium-derived relaxing factor is controversial in vivo but is usually present in vitro. On the other hand, it appears that endothelium-derived relaxing factor mediates flow-dependent vasodilation in both large vessels and in the microcirculation in vivo. The generation and release of endothelium-derived relaxing factor from endothelium may be abnormal in a variety of conditions including acute and chronic hypertension, atherosclerosis, and ischemia followed by reperfusion. Several mechanisms for these abnormalities have been identified. These include inability to generate endothelium-derived relaxing factor or destruction of endothelium-derived relaxing factor by oxidants after its release in the extracellular space. These abnormalities in endothelium-dependent relaxation may contribute to the vascular abnormalities in these conditions.
 ...
PMID:Endothelium-derived relaxing factors. A perspective from in vivo data. 217 Feb 74

Although indapamide has been used for many years as a first-line treatment of hypertension, it is only recently that some of its activities on the changes of the cardiovascular system, brought on by age and high blood pressure, have been studied. Indapamide appears to reduce blood pressure by a combined diuretic and direct vascular activity reducing vascular reactivity and total peripheral resistance. In addition, it has discrete effects on a number of interrelated systems that may protect the cardiovascular system. Indapamide reduces intracellular calcium levels, maintains magnesium ions, but reduces phosphate ions that may be involved in arterial rigidity. Circulating catecholamines remain unchanged but there is a reduction in normetanephrine, suggesting a reduction in sympathetic tone. It stimulates prostacyclin synthesis, increases levels of circulating prostacyclin, reduces platelet aggregation and stimulates the vasodilation elicited by endothelium-derived relaxing factor in the presence of bradykinin. In addition, it inhibits the formation of the vasoconstrictor prostanoid, thromboxane A2. The free radical scavenging activity of indapamide could also protect the vascular smooth muscle from the reperfusion injury of cerebral and myocardial ischemia. Indapamide induces a reduction in cerebral ischemia after carotid ligation. Unlike some other antihypertensives, it does not upset the high-density/low-density lipoprotein-cholesterol balance, reducing the possible risk of atherosclerosis. Moreover, the combination of binding to elastin and reduction in uptake of calcium and phosphate into the smooth muscle could be a mechanism for reducing arterial rigidity seen in the elderly and hypertensive patient. In hypertensive patients, these properties induce an improvement in arterial compliance, and in the long term a reduction in left ventricular hypertrophy. These pharmacologic and clinical results, together with a good antihypertensive efficacy and acceptability, suggest that indapamide may be a preferential agent in the long-term cardiovascular protection of the hypertensive patient.
 ...
PMID:Cardiovascular protective properties of indapamide. 218 50

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.
 ...
PMID:Endothelial control of vascular tone in large and small coronary arteries. 240 18

This study was undertaken to determine whether atherosclerosis impairs relaxations mediated by endothelium-derived relaxing factor (EDRF) in human coronary arteries. Epicardial coronary arteries were obtained from the hearts of cardiac transplantation patients with or without histologically documented coronary atherosclerosis (atherosclerotic arteries were from patients aged 42-55 years, nonatherosclerotic arteries were from patients aged 14-24 years). Transverse strip preparations were mounted in organ baths for isometric tension recording. Tension was induced with prostaglandins F2 alpha. Indomethacin (10(-5) M) was present to prevent possible interference from endogenously formed prostaglandins. The EDRF-mediated relaxations in response to substance P (10(-10) to 10(-8) M), bradykinin (10(-9) to 10(-7) M), and Ca2+-ionophore A23187 (10(-9) to 10(-7) M) were significantly attenuated in atherosclerotic arteries. In deendothelialized tissues these compounds had no effect. In contrast, endothelium-independent relaxations induced by isoprenaline (10(-7) to 10(-5) M) were not affected by atherosclerosis. Atherosclerotic arteries showed also normal relaxations with high concentrations of glyceryl trinitrate (10(-8) to 10(-7) M), but reduced relaxations with a lower concentration of the compound (10(-9) M). Acetylcholine (10(-7) to 10(-6) M) only produced endothelium-dependent relaxations in 8 of 60 arterial preparations (with or without atherosclerosis). In most of the arteries, it was a direct vasoconstrictor (which may have masked EDRF release in many cases). Omission of indomethacin from the bath solution increased the incidence of moderate acetylcholine-induced relaxations (9 of 16 preparations). It is concluded that atherosclerosis attenuates EDRF-mediated vasospasm and myocardial ischemia.
 ...
PMID:Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. 244 55

In canine and porcine coronary arteries, experimental atherosclerosis (induced by endothelial denudation followed by a high-cholesterol diet) potentiates the vasoconstrictor effects of histamine, serotonin, and ergonovine. In isolated human atherosclerotic coronary arteries, only hypersensitivity to histamine has been demonstrated. This discrepancy could be due to several factors. First, the atherosclerotic lesions in human vessels are different from those observed in the animal, since experimental atherosclerosis often corresponds only to the early stage of the disease in humans. Second, the human atherosclerotic coronary arteries were isolated mainly from patients with cardiac failure, a condition that alters the responses of coronary smooth muscle to vasoactive amines. With regard to endothelium-dependent vasodilators, marked attenuations of the relaxations to substance P, bradykinin, and the Ca2+ ionophore A23187 have been described in isolated human atherosclerotic arteries. Acetylcholine elicits variable responses in these preparations and even if the arteries are devoid of atherosclerotic lesions, it often fails to relax them. In addition to this endothelial dysfunction, severely atherosclerotic human coronary vessels exhibit a slightly decreased responsiveness to nitroglycerin and SIN-1 but not to forskolin. Another abnormality of the smooth muscle is a marked attenuated beta-adrenergic relaxation. Thus, atherosclerosis of human coronary vessels induces not only marked alterations in endothelium-dependent responses but also modifies the sensitivity to several endothelium-independent vasodilators.
 ...
PMID:Atherosclerosis and responses of human isolated coronary arteries to endothelium-dependent and -independent vasodilators. 248 97

Vasoconstrictor responses are augmented in porcine coronary arteries in hypercholesterolemia and atherosclerosis, leading to an occurrence of coronary vasospasm in the latter condition. The role of the endothelium in the vascular hyperreactivity in hypercholesterolemic and atherosclerotic coronary arteries was examined, particularly in response to aggregating and related vasoactive substances. Male Yorkshire pigs underwent balloon endothelial denudation of the left anterior descending coronary artery (LAD) and 2% high-cholesterol feeding for 10 weeks. Electron microscopic examination demonstrated a full lining of endothelial cells in the LAD and the left circumflex coronary artery (LCX). Endothelium-dependent responses were examined in vitro. In cholesterol-fed animals, endothelium-dependent relaxations to aggregating platelets, serotonin, ADP, bradykinin, thrombin, and the calcium ionophore A23187 were depressed in LAD (atherosclerosis), while the relaxations to aggregating platelets, serotonin and ADP were depressed in LCX (hypercholesterolemia). Serotonin-induced contractions were endothelium-dependently augmented in atherosclerotic LAD; the endothelium-dependent component of the contractions was inhibited by blockers of cyclooxygenase. Bioassay studies demonstrated a depressed release of endothelium-derived relaxing factor(s) from the atherosclerotic LAD in response to serotonin. These experiments indicate that the endothelium-dependent relaxations to aggregating platelets and related vasoactive substances are severely impaired in atherosclerosis and moderately impaired in hypercholesterolemia. Since coronary atherosclerosis was induced by a combination of balloon endothelial injury (and regeneration) and high-cholesterol feeding in this study, the combined effects of those factors must account for the severely impaired responses in atherosclerosis. The depressed release of the endothelium-derived relaxing factor(s) and the concomitant release of vasoconstrictor product(s) of cyclooxygenase appear to be responsible for the impaired relaxations.
 ...
PMID:Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis. 249 69

The effect of chronic oral defibrotide on platelet function, vascular PGI2 generation, atherosclerotic plaque formation and serum lipids was studied in rabbits. The animals were fed for 4 months a standard laboratory diet (150 g/day) with or without defibrotide (60 mg/kg/day) or a cholesterol-rich (1%) diet with or without defibrotide. Defibrotide significantly reduced the platelet reactivity ex vivo against collagen and ADP. This included a reduced aggregation response, thromboxane release and ATP secretion. Furthermore, the inhibition of platelet function and stimulation of platelet cAMP by iloprost, were significantly improved by defibrotide treatment. This was associated with an increased number of prostacyclin binding sites and enhanced PGI2 affinity in platelet membranes from these animals. Bradykinin stimulated PGI2 generation of segments of the thoracic aorta about 2-fold above control in both normo- and hypercholesterolemic rabbits. There was no difference in basal values between these groups but a more than 2-fold increase in either group by defibrotide treatment. Atherosclerotic plaque formation, determined by a subjective score, was found to be significantly reduced by defibrotide although the compound did not alter serum cholesterol levels. The data suggest potent and potentially valuable antiatherosclerotic effects of oral defibrotide: (i) normalization of platelet function by reduction of platelet hyperreactivity and improvement of the sensitivity towards prostacyclin, and (ii) stimulation of vascular PGI2 production.
Atherosclerosis 1989 Nov
PMID:Stimulation of vascular prostacyclin and inhibition of platelet function by oral defibrotide in cholesterol-fed rabbits. 251 13

Two of the many mediators synthesized by vascular endothelial cells (EC), are involved in maintaining the surface of the normal, healthy endothelium in a non-thrombogenic state. The first is prostacyclin, a product of arachidonic acid metabolism, discovered in 1976. This labile prostanoid, with a half life of approximately 3 minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Prostacyclin and its analogues are currently being tested in the clinic for cardiovascular diseases such as primary pulmonary hypertension. A number of drugs including defibrotide, nafazatrom, ronicol and cicletanine may exert their therapeutic effects by releasing prostacyclin from the EC. The second mediator discussed is endothelium-derived relaxing factor (EDRF), discovered in 1980, which also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Substances which stimulate release of EDRF include acetylcholine, bradykinin and ADP. EDRF is even more labile than prostacyclin with a half life counted in seconds. It has recently been identified as nitric oxide formed from L-arginine by an unknown mechanism. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. It is suggested that these mediators form the endothelial defence mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis. The peptide, endothelin is the third mediator under discussion. Characterised and synthesised in 1988, it is the most potent vasoconstrictor so far discovered. Three isomers of endothelin have been identified. Paradoxically, endothelin strongly releases both prostacyclin and EDRF thus modulating its own vasoconstrictor actions.
 ...
PMID:Vasoactive mediators derived from the endothelium. 251 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>