Decreased intrahepatic response to alpha(1)-adrenergic agonists in lipopolysaccharide-treated rats is located in the sinusoidal area and depends on Kupffer cell function.
OBJECTIVE
Livers from lipopolysaccharide-treated rats have a decreased vascular response to alpha(1)-adrenergic agonists due to an increased production of nitric oxide. Kupffer cells play a central role in the development of intrahepatic microvascular abnormalities during endotoxemia. We investigated the role of Kupffer cells in the intrahepatic vascular tone control in normal and endotoxemic rats.


METHODS
Twenty-four hours after pretreatment with gadolinium chloride (to eliminate/inactivate Kupffer cells) or saline, rats were treated with lipopolysaccharide or a second dose of saline. Six hours later, rats (under deep anesthesia) were submitted to liver perfusion with Krebs-Henseleit solution using a system that allowed the measurement of both perfusion and sinusoidal pressures. Dose-response curves to methoxamine (alpha(1)-adrenergic agonist) were obtained in the absence or the presence of the nitric oxide synthase inhibitor N-monomethyl-L-arginine.


RESULTS
Pretreatment with gadolinium did not change the intrahepatic vascular response to methoxamine in normal livers. Livers from lipopolysaccharide-treated rats showed a decreased sinusoidal vascular response to methoxamine and a 10-fold increase in nitric oxide production during liver perfusion. Either pretreatment with gadolinium or the presence of N-monomethyl-L-arginine in the perfusate restored the response to methoxamine and decreased the nitric oxide overproduction by more than 50%.


CONCLUSIONS
Kupffer cells neither mediate nor modulate the intrahepatic vascular response to alpha(1)-adrenergic agonists in normal livers. Reduction in intrahepatic vascular response to alpha(1)-adrenergic agonists in livers from lipopolysaccharide-treated rats is located in the sinusoidal area and depends on Kupffer cell function.
Lee
Chang-Hyeong
CH
Hepatic Hemodynamic Laboratory, VA Medical Center, West Haven, Connecticut 06516, USA.
Loureiro-Silva
Mauricio R
MR
Abraldes
Juan G
JG
Iwakiri
Yasuko
Y
Haq
Omar
O
Groszmann
Roberto J
RJ
D000322:Adrenergic Agonists / Q000494:pharmacology*; D000818:Animals; D004333:Drug Administration Routes; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005682:Gadolinium / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply / Q000187:drug effects; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000322:Adrenergic Agonists; D008070:Lipopolysaccharides; D005682:Gadolinium; D008729:Methoxamine; C038958:gadolinium chloride