-Original-

Inhibition of Nitric Oxide Synthase in Hyperdynamic Circulation of Rats with Early or Late Cirrhosis Secondary to Common Bile Duct Ligation

Yoshihito Kato¹, Yasumi Katsuta¹, Xue-Jun Zhang¹, Masaru Ohsuga¹, Toshio Akimoto², Akiko Miyamoto¹, Hirokazu Komeichi¹, Shuji Shimizu¹ and Kyoichi Mizuno¹

¹Divisions of Cardiology, Hepatology, Geriatrics, and Integrated Medicine, Department of Internal Medicine, Graduate School of Medicine, Nippon Medical School
²Division of Laboratory Animal Science, Nippon Medical School

Background/Aims: Preventing internal hemorrhage extends the lifespan of rats with chronic bile duct ligation (CBDL), a common animal model of portal hypertension. We investigated hemodynamics during the early and late stages of cirrhosis caused by CBDL. We also evaluated the hemodynamic influence of NO, which is the chief vasodilator in hyperdynamic syndrome, by administration of an NO synthase inhibitor (N^G-nitro-L-arginine methyl ester: L-NAME; 10 mg/kg).
Animals/Methods: In 24 Sprague-Dawley rats (9 sham rats and 15 CBDL rats), hemodynamics were assessed under conscious and unrestrained conditions 4 and 8 weeks after surgery. Before and 30 minutes after L-NAME administration, the cardiac index (CI) and regional blood flow were measured with the reference sample method using ¹⁴¹Ce- and ¹¹³Sn-microspheres (15 μm in diameter).
Results: A hyperdynamic systemic circulation and splanchnic hyperemia were observed after CBDL, and these changes increased with the progression of cirrhosis. L-NAME significantly diminished the hyperdynamic circulation and also reduced splanchnic hyperemia. In 4-week CBDL rats, a low hemoglobin concentration made an important contribution to the hyperdynamic circulation, and the portal collateral system collapsed when inflow to the portal territory was reduced by L-NAME treatment. In 8-week CBDL rats, systemic hemodynamics were closely linked to both the splanchnic circulation and the renal circulation before and after L-NAME administration, apart from hepatic artery blood flow.
Conclusion: The distinctive hemodynamic changes of portal hypertension were found in 8-week CBDL rats. Thus, 8-week CBDL rats may be a better animal model of human portal hypertension than 4-week CBDL rats.

J Nippon Med Sch 2011; 78: 146-155

Keywords
portal hypertension, nitric oxide, bile duct proliferation, splanchnic hyperemia, hyperdynamic circulation

Correspondence to
Yasumi Katsuta, MD, Division of Hepatology, Department of Internal Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
ykatsuta@nms.ac.jp

Received, August 26, 2010
Accepted, December 17, 2010