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

Endothelins (ET) are important regulators of the hepatic microcirculation that act through different receptor subtypes. We investigated functional significance of ET_B 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 ET_B mRNA and led to a shift in available receptors to the ET_B subtype. IRL 1620 (an ET_B agonist) increased portal pressure in a dose-dependent manner, and the increase in ET_B 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 ET_B 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 ET_B 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 ET_B1 -induced NOS activity attenuates ET_B2 (and presumably ET_A )-mediated portal pressor response and stellate cell constriction. Transcriptional activation of the ET_B gene may have a permissive effect on liver blood flow and protect against hepatocellular damage under pathophysiological conditions associated with endotoxemia.