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 t hat act through different receptor subtypes. We investigated functional sig nificance of ETB receptors in mediating microhemodynamic effects of ETs in normal and endotoxin (lipopolysaccharide [LPS])-primed rat liver. LPS primi ng (Escherichia coli O26:B6; 1 mg . kg(-1)) selectively increased ETB mRNA and led tot 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 presser re sponse in isolated livers. However, lactate dehydrogenase (LDH) release was attenuated and sinusoidal blood flow was better maintained upon ETB stimul ation in vivo. In isolated livers, portal constriction as well as release:o f LDH, were substantially increased in the presence of N-omega-nitro-L-argi nine 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 t he flow direction without significant sinusoid constriction. Sinusoidal flo w decreased even further after discontinuation of IRL 1620, Both effects we re mediated at extrasinusoidal sites that probably included postsinusoidal sites. However, after pretreatment with L-NAME, IRL 1620 evoked a significa nt sinusoidal constriction that colocalized with the body of the stellate c ell. We propose that ETB1-induced NOS activity attenuates ETB2 (and presuma bly ETA)-mediated portal presser response and stellate cell constriction. T ranscriptional activation of the ETB gene may have a permissive effect on l iver blood flow and protect against hepatocellular damage under pathophysio logical conditions associated with endotoxemia.