Portal hypertension (PHT) is characterized by splanchnic hyperemia caused by a reduction in mesenteric vascular resistance. Mediators of this hyperemia include nitric oxide (NO). This is based on several reports indicating a marked splanchnic hyporesponsiveness in PHT to vaso-constrictor stimuli, both in vitro and in vivo, and a subsequent reversal using specific inhibitors of NO synthase (NOS). The objective of this study was to determine directly if the generation of NO is altered in PHT vasculature. Thus, we compared NOS activity in the hyperemic vasculature of normal rabbits and rabbits with PHT (after undergoing partial portal vein ligation). Nicotinamide adenine dinucleotide phosphate diaphorase staining indicated the presence of NOS within the vascular endothelium. Ca(2+)-dependent NOS activity was significantly increased (P < .05) in PHT particulate fractions from the superior mesenteric artery and thoracic aorta, but not from the portal vein. There was no change in NOS activity within the cytosolic fractions. Arterial wall cyclic guanosine monophosphate (cGMP) levels and plasma nitrite levels were both significantly increased in PHT. These results show enhanced NOS activity in PHT hyperemic vessels concurrent with increased tissue cGMP levels. We conclude that enhanced NO synthesis contributes to the hyperdynamic circulation of PHT.

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(2015) Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice, Virulence, 6:5, 466-475, DOI: 10.1080/21505594.2015 Keywords: Anthrax, coagulation factor VIII, hemorrhage, lethal toxinMice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-offunction approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax.