Chronic ethanol consumption increases hepatic sinusoidal contractile response to endothelin-1 in the rat.
Recent evidence suggests that hepatic stellate cells function as liver-specific pericytes that are highly contractile in response to endothelin-1 (ET-1). Liver injury has been shown to lead to "activation" of stellate cells producing a phenotypic change to a more myofibroblastic cell type including loss of vitamin A and increased contractility. The present study was undertaken to test the effects of short-term chronic ethanol consumption (36% of total calories for 5 weeks according to the Lieber-DeCarli protocol) on hepatic vitamin A storage, expression of smooth muscle alpha-actin, and sinusoidal contractility in Sprague-Dawley rats. Using in vivo epifluorescence video microscopy, we quantified the number of sites of vitamin A fluorescence (purportedly stellate cells) and assessed sinusoidal microhemodynamics at baseline and during a 20-minute infusion period of ET-1 (1 pmol * 100 g body weight [bw]*1*min-1). Retinol and retinyl palmitate were measured after the experiment by means of high-pressure liquid chromatography (HPLC). A highly significant decrease in liver retinyl palmitate level (control: 622.5 +/- 50.9; ethanol: 273.0 +/- 38.0 microgram/g liver; P< .001) was found that correlated with a decrease in sites of vitamin A fluorescence (control: 531.4 +/- 76.1; ethanol: 141.1 +/- 30.2* mm-2; r = .82, P <.001). Concomitantly scattered expression of smooth muscle alpha-actin in sinusoids was observed. Although sinusoidal hemodynamics were not affected at baseline, a significant increase in sinusoidal contractility on endothelin-1 infusion (e.g., sinusoidal resistance [% of baseline value]: control: 10 minutes: 288.7 +/- 71.7, 20 minutes: 200.5 +/- 46.9; ethanol: 10 minutes: 1,916.0 +/- 701.7, 20 minutes: 656.8 +/- 103.3; P < .05 and .01, respectively) was observed. These data indicate that chronic ethanol consumption in this moderate model initiates stellate cell activation. Increased sinusoidal responsiveness to the vasoconstrictor ET-1 in vivo may contribute to the increased susceptibility of ethanol-fed rats to secondary stresses that increase ET-1 expression, such as endotoxemia.
Bauer
M
M
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
Paquette
N C
NC
Zhang
J X
JX
Bauer
I
I
Pannen
B H
BH
Kleeberger
S R
SR
Clemens
M G
MG
D000199:Actins / Q000096:biosynthesis; D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001835:Body Weight; D016232:Endothelins / Q000494:pharmacology*; D006439:Hemodynamics; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*; D014801:Vitamin A / Q000032:analysis
D000199:Actins; D016232:Endothelins; D014801:Vitamin A