Nitric oxide: a potential mediator of amino acid-induced renal hyperemia and hyperfiltration

The role of nitric oxide in the modulation of systemic and renal hemodynamics was examined by using N omega-monomethyl-L-arginine (L-NMMA, 110 micrograms/kg/min), a competitive inhibitor of the conversion of L-arginine to nitric oxide. L-NMMA or saline vehicle (9.6 microL/min) was infused intravenously into anesthetized euvolemic Munich-Wistar rats. After 30 min, L-NMMA resulted in a uniform increase in mean arterial blood pressure (111 +/- 1 to 128 +/- 2 mmHg; P less than 0.05) and a modest reduction in renal plasma flow rate (4.4 +/- 0.2 to 4.2 +/- 0.1 mL/min; P less than 0.05), without change in glomerular filtration rate (1.16 +/- 0.03 to 1.15 +/- 0.03 mL/min); vehicle had no effect on these renal parameters. These rats were then subdivided to receive an intravenous infusion (37 microL/min) of either 10% glycine, 11.4% mixed amino acids, or equiosmolar dextrose. L-NMMA pretreatment markedly attenuated glycine-induced hyperfiltration (10 +/- 6 versus 33 +/- 5%, L-NMMA versus vehicle; P less than 0.05) and obliterated the renal hyperemic response (-7 +/- 6 versus 16 +/- 4%, L-NMMA versus vehicle; P less than 0.05). L-NMMA also caused modest blunting of the mixed amino acid-induced hyperfiltration (18 +/- 4 versus 30 +/- 4%, L-NMMA versus vehicle; P = 0.056) but failed to curtail the renal hyperemia (16 +/- 6 versus 20 +/- 4%). Dextrose had no effect on glomerular filtration rate or renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiemetic properties of the 5HT3-receptor antagonist, gr38032f

GR38032F is a highly selective 5HT₃-receptor antagonist which inhibits vomiting induced by cisplatin, cyclophosphamide or X-radiation in the ferret. Since cisplatin selectively increased the levels of 5HT and 5HIAA in the intestinal mucosa, a possible site of the antiemetic action of GR38032F may be on 5HT₃-receptors on vagal afferents in the small intestine. The potent antiemetic action of GR38032F should be of clinical value in reducing the nausea and vomiting associated with radioterapy or chemotherapy of cancer.     

Different effects of prostacyclin and phentolamine on delivery-dependent O2 consumption and skin microcirculation after cardiac surgery

Inadequate tissue oxygen uptake autoregulation has been reported during the first hours after extracorporeal circulation for cardiac surgery. In the present study, we examined whether a dependence of oxygen consumption (VO2) on oxygen delivery (DO2) can be detected 24 hr after cardiac surgery using two different vasodilating agents. Cardiac output in triplicate was measured by thermodilution. Oxygen saturation of arterial and mixed venous blood was measured using a CO-oximeter. Oxygen consumption was assessed from the reverse Fick equation. In addition skin blood flow was assessed continuously by laser Doppler flowmetry. To investigate the VO2/DO2 relationship in 15 patients an increase in cardiac output and DO2 of at least 15% was achieved by systemic vasodilatation with iv prostacyclin (5-10 ng.kg-1.min-1) or phentolamine (5-10 g.kg-1.min-1). Infusion of phentolamine produced a 29 +/- 2% (mean +/- SE) increase in DO2 which was associated with a 20 +/- 6% increase in VO2. In contrast, prostacyclin produced a 22 +/- 3% increase in DO2 without change in VO2. Phentolamine did not alter skin microvascular blood flow, whereas prostacyclin increased skin microvascular blood flow by 33 +/- 3%. The results of the present study demonstrate a supply-dependency of VO2 in clinically stable patients 24 hr after cardiac surgery, suggesting the presence of an inadequate tissue O2 uptake autoregulation. The type of the vasodilator used to increase DO2 seems to play an important role in detecting such a supply-dependency of VO2, as well as changes of skin blood flow.     

Acute severe cardiac failure complicating myocardial infarction. Experience with 100 patients referred for consideration of mechanical left ventricular assistance.

One hundred patients were referred with suspected acute cardiac failure following acute myocardial infarction. The diagnosis was confirmed in 72: 31 of these patients underwent elective medical treatment, with 2 survivors (6%); 41 were accepted for counter pulsation, but 9 died before this could be initiated and another 2 died shortly after vain attempts to pass the balloon catheter were abandoned; 30 patients underwent counterpulsation with 14 hospital survivors (47%). Survivor status was usually good. Results of counter pulsation were better in patients who were not shocked (with 5/5 survivors) than in those who were in shock (with 9 of 25 survivors). Results support the view that counterpulsation (alone or combined with corrective surgery) may play an important role in the complications of myocardial infarction provided intervention is early.     

Nuclear RNA sequences coding for alpha and beta globins in erythroid cells: evidence for multiple intermediate molecules

The poly (A)-containing nuclear RNA from dimethylsulfoxide-induced Friend leukemia cells was fractionated by acrylamide gel electrophoresis in denaturing conditions and analyzed for alpha and beta globin RNA sequences. The results indicate that nuclear RNA contains one species of large-size RNA (0.6 X 10(6) daltons), which is the putative precursor for beta globin mRNA only. In addition, it was shown by electrophoretic analysis that the complex of RNA molecules not resolved by sucrose gradient centrifugation (11S) comprises sequences of decreasing size (0.34, 0.28, and 0.26 X 10(6) daltons), which might be the precursors of alpha and beta globin mRNA.     

The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal- cell-independent expansion and differentiation of human fetal pro-B cells in vitro

The effects of a novel cytokine FLK2/FLT3 ligand (FL) on human fetal bone marrow-derived CD34+CD19+ pro-B cells were analyzed in a stromal- cell-independent, serum-deprived culture system. FL, like interleukin-3 (IL-3), synergized with IL-7 in promoting pro-B cell growth, and differentiation of these cells into CD34-CD19+clgM+slgM- pre-B cells, whereas a small proportion of these cells even differentiate into more mature slgM+ B cells. In contrast, KIT ligand (KL) and granulocyte- macrophage colony-stimulating factor (GM-CSF) were ineffective in promoting IL-7-dependent pro-B cell growth and differentiation. Maximal levels of pro-B cell expansion, generally resulting in 15- to 30-fold increases in cellularity, were obtained in cultures supplemented with optimal doses of FL + IL-7 + IL-3. The addition of mouse bone marrow stromal cells further enhanced the proliferation and differentiation of pro-B cells obtained in the presence of these three cytokines. Under these conditions, cultures could be maintained for more than 4 weeks, and in general 40- to 50-fold increases in cell numbers were observed by 3 weeks of culture. The percentages of clgM+ and slgM+ B cells increased 1.5- to 3-fold and 2-fold, respectively, suggesting that stromal cells may provide additional costimulatory signals for human B- cell growth and differentiation that are different from IL-7, IL-3, and FL. Collectively, our results indicate that FL, in contrast to KL, strongly promotes long-term expansion and differentiation of human pro- B cells in the presence of IL-7 or in combination of IL-7 and IL-3, which is a novel property of this hematopoietic growth factor.     

STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation

Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases.