Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries

OBJECTIVE: Hydrogen peroxide (H2O2) produced by the vascular endothelium is a signaling molecule regulating vascular tone. We hypothesized that H2O2 derived from eNOS activity could play a physiological role in endothelium-dependent dilation of mouse cerebral arteries. METHODS: Simultaneous endothelium-dependent dilation and fluorescence-associated free radical (DCF-DA) or NO (DAF-2) production were recorded in isolated and pressurized (60 mm Hg) cerebral artery of C57Bl/6 male mice. RESULTS: Without synergism, N-nitro-L-arginine (L-NNA) or the H2O2 scavengers catalase, PEG-catalase and pyruvate reduced (P < 0.05) by 50% the endothelium-dependent dilation induced by acetylcholine (ACh). Simultaneously with the dilation, H2O2--but not NO--production, sensitive to either L-NNA or catalase, was detected. In cerebral arteries from C57Bl/6.eNOS-/- mice, catalase had no effect on ACh-induced dilation and no H2O2-associated fluorescence was observed. In C57Bl/6 mice, silver diethyldithiocarbamate (DETC), a superoxide dismutase (SOD) inhibitor, but not the specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (PTIO), prevented ACh-induced dilation and H2O2 production suggesting that eNOS-derived superoxide is an intermediate in the production of H2O2. The catalase-sensitive ACh-induced dilation was restored by the eNOS cofactor tetrahydrobiopterin (BH4). This reversal was associated with a NO-associated fluorescence sensitive to PTIO but not to catalase. Soluble guanylate cyclase inhibition with 1H-[1,2,4]-oxadiazole-4,3-aquinoxalin-1-one (ODQ) prevented the dilation induced by ACh and by exogenous H2O2. Lastly, L-NNA, PTIO and ODQ--but not DETC, catalase or pyruvate--increased the pressure-dependent myogenic tone, suggesting that eNOS produces NO at rest, but leads to H2O2 during muscarinic stimulation. CONCLUSION: H2O2-dependent dilation in mouse cerebral arteries appears to be a physiological eNOS-derived mechanism.     

The flow-volume curve. Expression of emptying as a function of venous distensibility

Mercury strain gauge venous occlusion plethysmography is a non invasive exploration of the lower limb venous hemodynamic. Classically, venous distensibility (delta V/V %) is expressed in terms of time during venous inflow (venous occlusion) and venous outflow (after cuff deflation). The authors proposed to express the total flow Q of the limb (obtained by a differentiator of the electric signal of the strain gauge) in terms of the venous distensibility (delta V/V %) whatever recording a top each second. This new representation Q = f(delta V/V) permit a more acute visualisation of the initial part of the venous emptying: more differentiation between venous drainage and systolic arterial waves, acceleration then deceleration of the venous emptying, return of the venous wall to its initial position later than venous emptying, active venous constriction. Some parameters are proposed to described this curve and the values obtained in 50 patients without and 10 patients with deep venous thrombosis are reported.     

Morphometric study of human hepatic cell modifications induced by fenofibrate

We have studied liver biopsies obtained in 12 hyperlipoproteinemic (HLP) patients (type II, 6; type IV, 6) treated with diet and fenofibrate, and in 15 patients (type II, 11; type IV, 4) receiving diet only. Electron microscopy of liver biopsies and the morphometric analysis according to the method of Weibel and Rohr showed mitrochondrial changes in patients treated with fenofibrate, these changes depending on the type of hyperlipoproteinemia. In type II HLP, we found a decreased volume of normal mitochondria (fenofibrate, 125.72 +/- 17.04 X 10(-3) cm3/cm3; diet only, 185.84 +/- 8.96 10(-3), P less than .05). In type IV HLP we found a decreased number of giant mitochondria (fenofibrate, 0.08 +/- 0.03 X 10(10) cm-3; diet only, 0.32 +/- 0.08 X 10(10) cm-3, P less than .05) and a decreased volume of altered mitochondria (fenofibrate, 6.00 +/- 1.44 X 10(-3) cm3/cm3; diet only, 13.61 +/- 1.17 X 10(-3), P less than .05). In contrast with the rodent studies, the present study shows no change in the number of volume of peroxisomes.     

Inhibition of growth hormone and thyrotropin release by growth hormone-release inhibiting hormone

Addition of increasing doses of synthetic growth hormone-release inhibiting hormone (GH-RIH) leads to a progressive decrease of the basal and N⁶monobutyryl cyclic AMP-,theophylline- and prostaglandin E₂-induced release of immunoreactive growth hormone (GH) and thyrotropin (TSH) release from rat anterior pituitary cells in monolayer culture. A halfmaximal effect is measured at 3 × 10^?9 M GH-RIH while a maximal inhibition to 10–20% of the control level is found at 1 × 10^?7 M. Using rat hemipituitaries and measurement of GH release by both polyacrylamide gel electrophoresis and radioimmunoassay, a maximal effect of GH-RIH was found in the first 5 min of incubation. The inhibitory effect of GH-RIH on GH release remained constant for at least 3 h. GH-RIH does not affect the basal or induced release of prolactin and luteinizing hormone nor the high K ⁺-induced release of GH and TSH.     

Rearrangement of BCR genes in malignant lymphoma.

The Philadelphia chromosome, originally thought to be associated solely with chronic myelogenous leukemia (CML), has since been identified in acute leukemias and in some cases of lymphoma. The Philadelphia chromosome results from reciprocal translocation of genetic material between chromosome 9 and 22 involving the c-abl and BCR genes respectively. Southern blot analysis of the BCR genes was carried out on biopsy specimens from 49 patients presenting with malignant lymphoma without a previously documented CML phase. In two patients, BCR gene rearrangements were detected in the malignant lymph nodes but not in the bone marrow samples. A third patient showed BCR gene rearrangements in the bone marrow but not in the lymph node. From this limited study, it seems that the overall incidence of BCR gene rearrangement in malignant lymphoma is similar to that observed in adult AML.