Citations

The objective of this study was to determine in conscious dogs the role of endothelium-derived nitric oxide in mediating the arterial pressure and renal response to a prolonged increment of sodium intake. After a control period of 3 days, an inhibitor of nitric oxide synthesis, NG-nitro-L-arginine-methyl ester, was infused intravenously during 5 consecutive days (0.1 micrograms/kg per minute). Sodium intake (80 mmol/d) did not change throughout the experiment in one group (n = 4). In another group (n = 6), 1 day after infusion of this inhibitor was started, sodium intake increased from 80 to 300 mmol/d during 4 consecutive days. Inhibition of nitric oxide synthesis in dogs with normal sodium intake induced a significant decrease in natriuresis and diuresis (P < .05) without changes in arterial pressure. However, in dogs treated with the nitric oxide synthesis inhibitor, mean arterial pressure increased from 95.2 +/- 3.3 to 106.2 +/- 4.0 mm Hg (P < .01) the first day that sodium intake was elevated and remained increased the following 3 days. In a different group of dogs (n = 5), the increment of sodium intake during 4 days did not induce changes in arterial pressure when nitric oxide synthesis was not inhibited. Cumulative sodium balance was higher (P < .01) in dogs treated simultaneously with the nitric oxide synthesis inhibitor and high sodium intake (158 +/- 21 mmol sodium) than in those treated only with the nitric oxide synthesis inhibitor (82 +/- 19 mmol sodium) or with high sodium intake (36 +/- 13 mmol sodium).(ABSTRACT TRUNCATED AT 250 WORDS)

Intrarenal infusion of acetylcholine in meclofenamate-treated dogs significantly increased renal blood flow, diuresis, and natriuresis. Intrarenal infusions of either NG-monomethyl-L-arginine (inhibitor of endothelium-derived relaxing factor formation), or L-arginine (precursor of endothelium-derived relaxing factor formation) did not modify basal levels of those parameters. However, the infusion of NG-monomethyl-L-arginine inhibited the acetylcholine-induced increases in renal blood flow and diuresis without affecting natriuresis, which increased significantly. The infusion of L-arginine failed to further enhance hemodynamic and excretory effects elicited by acetylcholine. The concomitant infusion of L-arginine and NG-monomethyl-L-arginine did not change renal blood flow, urine flow, or sodium excretion rate. L-Arginine administration prevented the inhibitory effect of NG-monomethyl-L-arginine on acetylcholine-induced renal vasodilatation and diuresis. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. The results indicate that the vasodilatory and diuretic responses to intrarenal acetylcholine in meclofenamate-treated dogs are largely dependent on endothelium-derived relaxing factor.

Depressed myocardial contractility with paradoxically increased oxygen consumption has been demonstrated in previous studies of pressure overload hypertrophy. To determine whether altered mitochondrial respiration participates in the abnormal energetics of this muscle, right ventricular hypertrophy (RVH) was produced in 12 cats by pulmonary artery banding. A polarographic muscle bath was used to study eight control and eight RVH papillary muscles, and the respiration of mitochondria isolated from these right ventricles was characterized. RVH muscles demonstrated depressed force-velocity and length-tension curves. The myocardial oxygen consumption per gram of peak active tension was increased from 0.65 ± 0.05 nliters/mg beat -1 (control) to 1.10±0.07 nliters/mg beat -1 (RVH) ( P <0.001). Abnormal mitochondrial respiration was shown by an increase in the rate of state 4 oxygen consumption from 12.5±0.8 natoms/mg min -1 (control) to 19.9±0.8 natoms/mg min -1 (RVH) ( P < 0.001). The altered oxygen cost of active isometric tension in the RVH muscles was linearly correlated with the altered rate of mitochondrial state 4 oxygen consumption ( r = 0.91). Ruthenium red, a compound that blocks mitochondrial calcium uptake, reduced the rate of RVH state 4 oxygen consumption to the control level. The present study suggests a mechanism for the abnormal myocardial oxygen consumption in pressure overload hypertrophy and relates it to nonphosphorylating mitochondrial respiration linked to calcium transport.

In isolated canine papillary muscle-false tendon preparations it was possible by selecting the pattern of stimulation to obtain conduction block within the peripheral distribution of the Purkinje network. Action potentials recorded just proximal to the site of block were always extremely brief in duration; refractory periods were abbreviated accordingly. When propagation from specialized fibers to muscle fibers was made very critical, conduction block occurred at some Purkinje-muscle junctions while propagation continued through others. Under these conditions very early reentrant activity could be obtained in terminal Purkinje fibers. With proper timing, the impulse propagated back to the false tendon and emerged as a closely coupled extrasystole. Occasionally, the activity returned again to muscle and resulted in a double reentry. Electrotonic shortening of action potentials of Purkinje fibers at relatively long distances upstream from a site of block facilitated the reentry of proximal elements. Partial reentry of the Purkinje system created conditions favoring fractionation of the reentrant wave front.

Abstract —In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng · kg −1 · min −1 , which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F 2α (F 2 -isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F 2 -isoprostanes. F 2 -isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F 2 -isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88 , CARD11 , EZH2 , and CREBBP . We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B , MLL2 , BTG1 , GNA13 , ACTB , P2RY8 , PCLO , and TNFRSF14 . Further, we show that BCL2 mutations commonly occur in patients with BCL2 / IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS , BRAF , and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.