A liver-specific nitric oxide donor improves the intra-hepatic vascular response to both portal blood flow increase and methoxamine in cirrhotic rats.
OBJECTIVE
A decreased intra-hepatic nitric oxide (NO) production participates on the pathogenesis of portal hypertension in cirrhosis. We tested the hemodynamic effects of a liver-specific NO donor (NCX-1000) derived from ursodeoxycholic acid in portal hypertensive cirrhotic rats.


METHODS
After a 14-day treatment with ursodeoxycholic acid or NCX-1000 by gavage, ascitic cirrhotic rats (CCl4-induced) were used in two studies: (1) in vivo mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery (SMA) blood flow measurements before and during progressive blood volume expansion (blood infusion); and (2) in situ liver perfusion to obtain dose/response curves to methoxamine (alpha1-adrenergic agonist) and flow/pressure curves.


RESULTS
Basal heart rate, MAP, and PP were similar in both groups. During blood infusion, similar MAP and SMA flow increases were observed in both groups; however, PP increase observed in control rats was blunted in NCX-1000 treated rats (P=0.015). In liver perfusions, flow/pressure curves were similar in both groups; however, NCX-1000-treated livers showed a lower response to methoxamine (P=0.016). cGMP concentration in NCX-1000-treated livers was higher (P=0.015) than in controls.


CONCLUSIONS
Treatment with a liver-specific NO donor improves the portal system adaptability to portal blood flow increase and ameliorates the intra-hepatic response to methoxamine in cirrhotic rats.
Loureiro-Silva
Mauricio R
MR
Hepatic Hemodynamic Laboratory, Digestive Diseases Section/111H, VA Medical Center, 950 Campbell Avenue, West Haven, CT 06516, USA.
Cadelina
Gregory W
GW
Iwakiri
Yasuko
Y
Groszmann
Roberto J
RJ
D000818:Animals; D004347:Drug Interactions; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000502:physiology; D008729:Methoxamine / Q000494:pharmacology*; D009566:Nitrates / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011169:Portal Vein / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014580:Ursodeoxycholic Acid; D008729:Methoxamine