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At least 1,513 records · Page 84Linked to original sources
PubMed1998

Importance of endothelial function in mediating the benefits of lipid-lowering therapy.

Trials of lipid lowering by various methods have clearly demonstrated the benefits, clinically and angiographically. Evidence of slowed arterial disease progression and even regression has been convincing but modest, at best. For example, among those treated intensively in the Familial Atherosclerosis Treatment Study (FATS), the mean improvement in proximal stenosis severity was <1% per patient, and only 12% of all lesions showed convincing regression. Despite these modest arterial benefits, the associated reductions in major cardiovascular events have been surprisingly great (24-35% in 3 recent large trials and > or =50% in angiographic trials using combination therapies). The process of plaque disruption helps explain this discrepancy. Disruption can be predicted by a large accumulation of core lipid in the plaque and a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics comprise only 10-20% of the overall lesion population but account for 60-90% of the acute clinical events. Lipid-lowering therapy has beneficial effects on these "high-risk" features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes lipids from this relatively small but dangerous subgroup of fatty lesions, effectively stabilizing them.

Coronary Artery Disease↗
PubMed2000

Improvement by phosphoramidon of damaged endothelial function in porcine coronary artery.

BACKGROUND: The bradykinin (BK)-induced endothelium-dependent relaxation is impaired in the presence of elevated potassium concentration enhancing the vasospastic tendency of large coronary arteries. Inhibition of the angiotensin-converting enzyme responsible for bradykinin degradation was found to enhance the endothelium-dependent relaxation by BK. The aim of the present study was to investigate the effect of phosphoramidon, known to inhibit a BK-metabolizing neutral endopeptidase enzyme, on relaxation of porcine-isolated coronary artery in depolarizing solution. METHODS: Endothelium intact porcine coronary artery rings were studied in organ chambers. The rings were isometrically contracted with potassium chloride (30 mmol/L) and the response to BK (1 to 1,000 nmol/L)-induced relaxation was investigated in the presence of nitric oxide synthase inhibitor Nomega-nitro-L-arginine (300 micromol/L) alone and in combination with the cyclooxygenase inhibitor indomethacin (10 micromol/L), and that of the inhibitor of calcium-dependent potassium channels tetraethylammonium (7 mmol/L). Under these conditions, phosphoramidon (10 micromol/L), an inhibitor of a neutral endopeptidase enzyme (EC.3.4.24.11.), which is responsible for the degradation of BK, was used to enhance the endothelium-dependent relaxation. RESULTS: Phosphoramidon potentiated the maximum vasorelaxant effect of BK in Nomega-nitro-L-arginine (control 26.6%+/-10.86% versus phosphoramidon 49.05%+/-4.52%; n = 6, p < 0.05) or in Nomega-nitro-L-arginine + indomethacin-pretreated rings (control 20.7%+/-9.92% versus phosphoramidon 42.0%+/-12.26%; n = 5, p < 0.05) and this increased vasodilation was not modified by tetraethylammonium. CONCLUSIONS: In the present study phosphoramidon potentiated the effect of BK in the absence of nitric oxide and prostaglandins in porcine-isolated coronary artery. This effect did not depend on tetraethylammonium-sensitive potassium channels. Phosphoramidon may be a useful pharmacologic tool for preserving the vasorelaxing capacity of coronary arteries after cardioplegia.

Animals↗
PubMed1997

Hyperkalemia exposure impairs EDHF-mediated endothelial function in the human coronary artery.

BACKGROUND: My colleagues and I have found in the porcine coronary artery that the pathway other than the nitric oxide (NG-nitro-L-arginine [L-NNA]-sensitive) and cyclooxygenase (indomethacin-sensitive) pathways of endothelium-dependent relaxation, related to the endothelium-derived hyperpolarizing factor (K+ channel-related), are altered after exposure to hyperkalemia. The present study was designed to examine whether this effect exists in the human coronary artery. METHODS: Coronary artery rings obtained from explanted fresh human hearts were studied in organ chambers under physiologic pressure. The endothelium-dependent relaxation in response to calcium ionophore A23187 was studied in U46619 (30 nmol/L)-induced precontraction in the presence of the cyclooxygenase inhibitor indomethacin (7 mumol/L) and the nitric oxide biosynthesis inhibitor L-NNA (300 mumol/L). The effect of incubation with 20 mmol/L K+ for 1 hour on the relaxation was examined in other coronary rings. RESULTS: In control rings, A23187 induced a maximal relaxation of 50.7% +/- 3.2% (n = 6). After 1 hour of exposure to 20 mmol/L K+, the relaxation was reduced to 30.4% +/- 4.6% (n = 6; p = 0.005). Incubation with hyperkalemia also significantly reduced the sensitivity (increased effective concentration that caused 50% of maximal relaxation) of the indomethacin- and L-NNA-resistant relaxation (-7.37 +/- 0.17 versus -8.28 +/- 0.27 log mol/L; p = 0.019). CONCLUSIONS: Exposure to hyperkalemia reduces the indomethacin- and L-NNA-resistant, endothelium-dependent (endothelium-derived hyperpolarizing factor-related) relaxation in the human coronary artery. This suggests that the previously proposed mechanism of coronary dysfunction after exposure to cardioplegic and organ preservation solutions in animal vessels is also valid in the human heart.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2003

Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells.

Reactive oxygen species-induced reperfusion injury of the brain is an important cause of neonatal morbidity and mortality following perinatal hypoxia-ischemia. Deferoxamine, allopurinol and oxypurinol have previously been shown to be neuroprotective in vivo during or directly after hypoxia-ischemia. To further characterize and more precisely elucidate whether the neuroprotective properties of these agents are mediated via neuronal and glial cells, or whether endothelial cells contribute to this effect, we tested their ability to protect CA1 neurons in organotypic hippocampal slices. Hippocampal slices obtained from 8-day-old rats were cultured for 7 days and exposed to oxygen/glucose deprivation for 50 min, or used as control slices. Cell damage was assessed at 48 h after oxygen/glucose deprivation using propidium iodide staining. At different time points following oxygen/glucose deprivation we administered dizocilpine, 6-cyano-7-nitroquinoxaline-2,3-dione, and alpha-phenyl-N-tert-butyl nitrone for validation purposes. Deferoxamine, allopurinol or oxypurinol were used as test substances. As expected, 89% and 98% protection was demonstrated with dizocilpine present during or during/after oxygen/glucose deprivation resp. alpha-Phenyl-N-tert-butyl nitrone administered during/after oxygen/glucose deprivation provided 44% protection. However, iron chelation with deferoxamine and inhibition of xanthine oxidase by allopurinol or oxypurinol did not confer neuroprotection. The neuroprotective effect of deferoxamine, allopurinol or oxypurinol, as seen in vivo, may be obtained via inhibition of the production of damaging factors by blood born substances or endothelial cells.

Allopurinol↗