title: iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats.
abstract: Portal hypertension, a major complication of cirrhosis, is caused by both increased portal blood flow due to arterial vasodilation and augmented intrahepatic vascular resistance due to sinusoidal constriction. In this study, we examined the possible involvement of resident macrophages in the tone regulation of splanchnic blood vessels using bile duct ligated (BDL) portal hypertensive rats and an in vitro organ culture method. In BDL cirrhosis, the number of ED2-positive resident macrophages increased by two- to fourfold in the vascular walls of the mesenteric artery and extrahepatic portal vein compared with those in sham-operated rats. Many ED1-positive monocytes were also recruited into this area. The expression of inducible nitric oxide (NO) synthase (iNOS) mRNA was increased in the vascular tissues isolated from BDL rats, and accordingly, nitrate/nitrite production was increased. Immunohistochemistry revealed that iNOS was largely expressed in ED1-positive and ED2-positive cells. We further analyzed the effect of iNOS expression on vascular smooth muscle contraction using an in vitro organ culture system. iNOS mRNA expression and nitrate production significantly increased in vascular tissues (without endothelium) incubated with 1 μg/ml lipopolysaccharide (LPS) for 6 h. Immunohistochemistry indicated that iNOS was largely expressed in ED2-positive resident macrophages. α-Adrenergic-stimulated contractility of the mesenteric artery was greatly suppressed by LPS treatment and was restored by N(G)-nitro-L-arginine methyl ester (NO synthase inhibitor); in contrast, portal vein contractility was largely unaffected by LPS. Sodium nitroprusside (NO donor) and 8-bromo-cGMP showed greater contractile inhibition in the mesenteric artery than in the portal vein with decreasing myosin light chain phosphorylation. In the presence of an α-adrenergic agonist, the mesenteric artery cytosolic Ca(2+) level was greatly reduced by sodium nitroprusside; however, the portal vein Ca(2+) level was largely unaffected. These results suggest that the induction of iNOS in monocytes/macrophages contributes to a hypercirculatory state in the cirrhosis model rat in which the imbalance of the responsiveness of visceral vascular walls to NO (mesenteric artery >> portal vein) may account for the increased portal venous flow in portal hypertension.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajita
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Masateru
authors.initials: M
authors.lastname: Iizuka
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006975:Hypertension, Portal / Q000201:enzymology / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000503:physiopathology; D008264:Macrophages / Q000201:enzymology* / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology / Q000503:physiopathology; D009000:Monocytes / Q000201:enzymology / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology*; D018994:Myosin Light Chains / Q000378:metabolism / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D011169:Portal Vein / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D018994:Myosin Light Chains; D009566:Nitrates; D014665:Vasodilator Agents; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester