Functional significance of endothelin B receptors in mediating sinusoidal and extrasinusoidal effects of endothelins in the intact rat liver

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Abstract
Endothelins (ET) are important regulators of the hepatic microcirculation that act through different receptor subtypes. We investigated functional significance of ETB receptors in mediating microhemodynamic effects of ETs in normal and endotoxin (lipopolysaccharide [LPS])-primed rat liver. LPS priming (Escherichia coli O26:B6; 1 mg · kg−1) selectively increased ETB mRNA and led to a shift in available receptors to the ETB subtype. IRL 1620 (an ETB agonist) increased portal pressure in a dose-dependent manner, and the increase in ETB expression was associated with prolonged portal pressor response in isolated livers. However, lactate dehydrogenase (LDH) release was attenuated and sinusoidal blood flow was better maintained upon ETB stimulation in vivo. In isolated livers, portal constriction as well as release of LDH, were substantially increased in the presence of N ω-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthase (NOS). In vivo microscopic assessment of sinusoidal perfusion during ETB stimulation revealed a disruption of the flow pattern including frequent reversal of the flow direction without significant sinusoid constriction. Sinusoidal flow decreased even further after discontinuation of IRL 1620. Both effects were mediated at extrasinusoidal sites that probably included postsinusoidal sites. However, after pretreatment with l-NAME, IRL 1620 evoked a significant sinusoidal constriction that colocalized with the body of the stellate cell. We propose that ETB1-induced NOS activity attenuates ETB2 (and presumably ETA)-mediated portal pressor response and stellate cell constriction. Transcriptional activation of the ETB gene may have a permissive effect on liver blood flow and protect against hepatocellular damage under pathophysiological conditions associated with endotoxemia.

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