Lack of effect of norfloxacin on hyperdynamic circulation in bile duct-ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho-kinase?
OBJECTIVE
In cirrhosis, portal hypertension is maintained by splanchnic vasodilation owing to overproduction of the vasodilator nitric oxide (NO) and defective contractile signalling by Rho-kinase. NO overproduction is partially caused by bacterial translocation from the gut to mesenteric lymph nodes. However, the effects of intestinal bacterial decontamination on hyperdynamic circulation or vascular contractility are unknown. We investigated the haemodynamic and vascular effects of norfloxacin in rats with secondary biliary cirrhosis.


METHODS
Cirrhosis was induced by bile duct ligation (BDL). One group was treated with norfloxacin (20 mg/kg/day, 5 days, orally). Bacterial growth in the lymph nodes was determined on blood agar plates. Invasive haemodynamic measurements were combined with coloured microspheres. Aortic contractility was assessed myographically. Protein expression/phosphorylation was examined by Western blot analysis.


RESULTS
Norfloxacin treatment of BDL rats abolished bacterial translocation to mesenteric lymph nodes. BDL rats had hyperdynamic circulation, including portal hypertension and splanchnic vasodilation. None of these parameters was changed by norfloxacin, although norfloxacin reduced endothelial NO synthase expression and phosphorylation. The latter was associated with a diminished activity of protein kinase G (PKG), which mediates NO-induced vasodilation. However, norfloxacin had no effect on aortic contractility to methoxamine or Ca2+, or the aortic expression of RhoA, Rho-kinase and beta-arrestin 2, or the phosphorylation of the Rho-kinase substrate moesin.


CONCLUSIONS
Short-term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity.
Hennenberg
Martin
M
Department of Internal Medicine I, University of Bonn, Bonn, Germany. martin.hennenberg@ukb.uni-bonn.de
Trebicka
Jonel
J
Buecher
Doris
D
Heller
Jörg
J
Sauerbruch
Tilman
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000502:physiology; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D004576:Electromyography; D006975:Hypertension, Portal / Q000209:etiology; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000188:drug therapy*; D008198:Lymph Nodes / Q000187:drug effects / Q000382:microbiology*; D008297:Male; D008863:Microspheres; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009643:Norfloxacin / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D009643:Norfloxacin