Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)
Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate highthroughput screen, we identified a series of isothiazolonebased HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP -responsive element binding protein -binding protein -associated factor (PCAF) and p300 (1 to >50 Mmol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 Mmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2 -48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of A-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition. [Mol Cancer Ther 2005;4(10):1521 -32]
Hydrogen peroxide (H(2)O(2)) is a proposed endothelium-derived hyperpolarizing factor and metabolic vasodilator of the coronary circulation, but its mechanisms of action on vascular smooth muscle remain unclear. Voltage-dependent K(+) (K(V)) channels sensitive to 4-aminopyridine (4-AP) contain redox-sensitive thiol groups and may mediate coronary vasodilation to H(2)O(2). This hypothesis was tested by studying the effect of H(2)O(2) on coronary blood flow, isometric tension of arteries, and arteriolar diameter in the presence of K(+) channel antagonists. Infusing H(2)O(2) into the left anterior descending artery of anesthetized dogs increased coronary blood flow in a dose-dependent manner. H(2)O(2) relaxed left circumflex rings contracted with 1 muM U46619, a thromboxane A(2) mimetic, and dilated coronary arterioles pressurized to 60 cmH(2)O. Denuding the endothelium of coronary arteries and arterioles did not affect the ability of H(2)O(2) to cause vasodilation, suggesting a direct smooth muscle mechanism. Arterial and arteriolar relaxation by H(2)O(2) was reversed by 1 mM dithiothreitol, a thiol reductant. H(2)O(2)-induced relaxation was abolished in rings contracted with 60 mM K(+) and by 10 mM tetraethylammonium, a nonselective inhibitor of K(+) channels, and 3 mM 4-AP. Dilation of arterioles by H(2)O(2) was antagonized by 0.3 mM 4-AP but not 100 nM iberiotoxin, an inhibitor of Ca(2+)-activated K(+) channels. H(2)O(2)-induced increases in coronary blood flow were abolished by 3 mM 4-AP. Our data indicate H(2)O(2) increases coronary blood flow by acting directly on vascular smooth muscle. Furthermore, we suggest 4-AP-sensitive K(+) channels, or regulating proteins, serve as redox-sensitive elements controlling coronary blood flow.
Objective-We tested the hypothesis that hydrogen peroxide (H 2 O 2 ), the dismutated product of superoxide (O 2 ⅐Ϫ ), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O 2 ⅐Ϫ and H 2 O 2 production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H 2 O 2 . Methods and Results-The production of O 2⅐Ϫ is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O 2 ⅐Ϫ during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-ptrifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O 2 ⅐Ϫ production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O 2 ⅐Ϫ production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67Ϯ8% percent of maximal dilation) that was significantly reduced by catalase (5Ϯ0.5%, PϽ0.05) or the antagonist of Kv channels, 4-aminopyridine (18Ϯ4%, PϽ0.05). In intact animals, tissue concentrations of H 2 O 2 are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H 2 O 2 by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus pO 2 . Conclusions-Taken together, our results demonstrate that O 2⅐Ϫ is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H 2 O 2 . Our results further suggest that the production of H 2 O 2 in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption. Key Words: reactive oxygen species Ⅲ coronary circulation Ⅲ vasodilation Ⅲ microcirculation T he coupling of blood flow to metabolism is the most important vasomotor adjustment for the regulation of oxygen delivery to metabolically active organ systems. This matching, termed metabolic dilation, or metabolic or active hyperemia, is critical to ensure adequate oxygen delivery for aerobic metabolism and adequate organ function. 1 Although the factor or factors responsible for the coupling of flow to metabolism have been actively pursued for decades, no metabolite has been casually linked to the process of metabolic hyperemia or has withstood critical evaluation. 1-3 Most investigations have pursued the idea that the metabolic regulation of flow is a negative feedback pathway, in which an imbalance between oxygen supply (delivered via flow) and oxygen demands, ie, demands exceed supply, results in the production of a metabolic dilator. The adenosine hypothesis was such a scheme, in which oxygen demands, in excess of supply would increase the production of adenosine through hydro...
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