Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver.

Abstract

Heme oxygenase (HO)-1 is up-regulated after ischemia/reperfusion and contributes to maintenance of hepatic perfusion and integrity. Blockade of HO-1 leads to an increased portal pressor response in the stress-exposed liver. We tested whether the increase in portal pressure reflects unmasking of a concomitant up-regulation of the vasoconstrictor endothelin (ET)-1. Hemorrhagic shock induced messenger RNAs encoding HO-1 (16-fold) and ET-1 (9-fold) with a similar time course in the liver. At maximum induction of both mediators, rats received either vehicle or the endothelin ET(A/B) antagonist bosentan (10 mg/kg intravenously). Subsequently, the HO pathway was blocked in all animals by tin-protoporphyrin (SnPP)-IX (50 micromol/kg intravenously). Portal and sinusoidal hemodynamics were measured using microflow probes and intravital microscopy, respectively. Blockade of the HO pathway led to a significant increase in portal resistance (sham/SnPP-IX, 0.17 +/- 0.046 mm Hg. min. mL(-1); shock/vehicle/SnPP-IX, 0.57 +/- 0.148 mm Hg. min. mL(-1); P <.05) and a decrease in sinusoids conducting flow (shock/vehicle/SnPP-IX: baseline, 28.3 +/- 0.85 sinusoids/mm; 10 minutes after SnPP-IX, 23.1 +/- 1.09 sinusoids/mm; P <.05). Intravital microscopy showed narrowing of failing sinusoids colocalizing with stellate cells after blockade of the HO pathway. Blockade of ET(A/B) receptors attenuated the increase in portal resistance (shock/bosentan/SnPP-IX, 0.29 +/- 0.051 mm Hg. min. mL(-1)) and prevented sinusoidal perfusion failure (shock/bosentan/SnPP-IX: baseline, 28.2 +/- 0.97 sinusoids/mm; 10 minutes after SnPP-IX, 28.8 +/- 1.18 sinusoids/mm) as well as sinusoidal narrowing. In conclusion, a functional interaction of the up-regulated vasodilatory HO system and the vasoconstrictor ET-1 on the sinusoidal level exists under stress conditions. Both mediator systems affect sinusoidal diameter via direct action on hepatic stellate cells in vivo.

• Authors: Hauke Rensing, Inge Bauer, Jian X Zhang, Markus Paxian, Benedikt H J Pannen, Yukihiro Yokoyama, Mark G Clemens, Michael Bauer
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 36 Issue 6 Pg. 1453-65 (Dec 2002) ISSN: 0270-9139 [Print] United States
• PMID: 12447872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Endothelin Receptor Antagonists
• Endothelin-1
• Enzyme Inhibitors
• Metalloporphyrins
• Nitric Oxide Donors
• Protoporphyrins
• Receptors, Endothelin
• Sulfonamides
• Molsidomine
• tin protoporphyrin IX
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• Bosentan

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Bosentan
• Dose-Response Relationship, Drug
• Endothelin Receptor Antagonists
• Endothelin-1 (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (physiology)
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, genetics, metabolism)
• Heme Oxygenase-1
• Liver (metabolism)
• Liver Circulation (drug effects, physiology)
• Male
• Metalloporphyrins (pharmacology)
• Molsidomine (pharmacology)
• Nitric Oxide Donors (pharmacology)
• Portal Vein (physiology)
• Protoporphyrins (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Endothelin (metabolism)
• Resuscitation
• Shock, Hemorrhagic (metabolism)
• Stress, Physiological (metabolism)
• Sulfonamides (pharmacology)