irl-1620 and Hypertension--Portal

The present study was undertaken to investigate hepatic microcirculatory response following partial portal vein ligation (PPVL) in rats. Portal pressure was markedly increased 2-6 wk after PPVL, but no significant reduction in sinusoidal perfusion and hepatocellular injury were detected. However, marked neovascularization was observed in PPVL rats using intravital microscopy and scanning electron microscopy (SEM). Extremely high red blood cell velocity (2,000-4,900 microm/s) was seen in these vessels. Injection of fluorescein sodium via the carotid artery revealed that the neovessels originated from the hepatic arterial vasculature. This was further confirmed by clamping the common hepatic artery and phenylephrine injection from the carotid artery. These vessels maintained sufficient flow after massive sinusoidal shutdown elicited by the portal infusion of endothelin receptor B agonist IRL-1620. SEM also showed extensive neovascularization at the hilum. Additionally, clamping the portal vein decreased sinusoidal perfusion only by 9.5% in PPVL, whereas a 71.2% decrease was observed in sham. These results strongly suggest that the liver maintains its microcirculatory flow by vascular remodeling from the hepatic arterial vasculature following PPVL.

Topics: Alanine Transaminase; Animals; Blood Flow Velocity; Corrosion Casting; Endothelins; Hepatic Artery; Hypertension, Portal; L-Lactate Dehydrogenase; Ligation; Liver Circulation; Male; Microcirculation; Microscopy, Electron, Scanning; Neovascularization, Physiologic; Peptide Fragments; Phenylephrine; Portal Vein; Rats; Rats, Sprague-Dawley; Surgical Instruments; Vasoconstrictor Agents

Endothelin (ET) is one of the most active vascular regulators in the liver. It is unknown how partial portal vein ligation (PPVL) induced prehepatic portal hypertension influences the response of the liver to ET and its agonists. Therefore, this study was conducted to determine the expression of ET receptors and its functional significance after PPVL.. Competitive receptor binding study and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) were performed using liver homogenates after 2 weeks of PPVL or sham operation in rats. Hepatic microcirculation was evaluated in vivo using intravital microscopy.. Although there was no significant difference in dissociation constant (Kd) and total amount of receptors (Bmax) between sham and PPVL, the proportion of ET(B) receptor was significantly increased in PPVL. RT-PCR analysis confirmed the up-regulation of ET(B) receptors demonstrated by the competitive receptor binding assay. In the functional study, infusion of ET(B) agonist (IRL 1620) in a low dosage did not change the hepatic microcirculation in sham but strongly constricted the sinusoids leading to a reduction of sinusoidal perfusion in PPVL.. These results suggest that prehepatic portal hypertension may predispose the hepatic microcirculation to dysregulation in stress conditions where ET is upregulated.

Topics: Animals; Binding, Competitive; Endothelins; Hemodynamics; Hypertension, Portal; Liver Circulation; Microcirculation; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger