Potentiated Hepatic Microcirculatory Response to Endothelin-1 During Polymicrobial Sepsis

Abstract

We conducted this study to elucidate the role of endothelins (ET-1) in mediating the hepatic microcirculatory dysfunction observed in response to sepsis. Following 24 h of cecal ligation and puncture (CLP), we performed intravital microscopy both in vivo and on isolated perfused livers. Portal resistance increased in response to ET-1 in both sham and septic rats, with no significant difference between the two in either in vivo or in isolated livers. Sinusoidal volumetric flow (Qs) was evaluated using red blood cell velocity (V(RBC)) and sinusoidal diameter (Ds) to determine microvascular hemodynamic integrity. Qs decreased in response to ET-1 in livers from CLP rats compared with sham (P < 0.05, CLP vs. sham) in both in vivo and isolated livers. In vivo infusion of ET-1 resulted in greater constriction of sinusoids in the CLP group compared with sham (P < 0.05), resulting in higher sinusoidal resistance. Microvascular hyper-responsiveness was accompanied by hepatocellular injury in CLP rats, but not in sham rats. RT-PCR was performed to measure mRNA levels of ET-1, its receptors ET(A) and ET(B), inducible and constitutive nitric oxide (NO) synthase (iNOS and eNOS, respectively), and heme oxygenase 1 (HO-1). After CLP, both ET-1 and ET(B) mRNA increased, whereas ET(A) mRNA tended to decrease, although the change was not statistically significant. Livers from CLP rats showed no significant change in levels of eNOS mRNA, but showed a significant increase in iNOS expression (13.5-fold over sham). There was no change in the level of HO-1 mRNA between sham and CLP groups. Taken together, these results suggest that sepsis sensitizes the hepatic microcirculation to ET-1. More importantly, an impaired microcirculatory flow due to ET-1 in sepsis contributes to hepatic injury. Further, localized imbalances between endothelins and NO may mediate the altered microvascular response during sepsis.

Role of Kupffer Cells in Vasoregulatory Gene Expression During Endotoxemia

“…Recent studies indicate that the putative ET B1 receptors mediate the constriction of the hepatic sinusoids, but the effect tends to be masked by the concomitant vasodilatory actions of NO (Higuchi and Satoh, 1997). Along with the increase in ET-1 mRNA, expression of its receptor, ET B , was significantly increased in endotoxemia, which is consistent with other studies that reported a higher ET B receptor proportion during endotoxemia (Baveja et al, 2002). The increase in ET B receptor expression was augmented by GdCl 3 .…”

Mixed Endothelin Receptor Antagonism With Tezosentan Improves Intestinal Microcirculation in Endotoxemic Shock

“…The increased vascular resistance in the portal circulation is due to a combination of both increased production of ET-1 and an increased vascular responsiveness to ET-1 [38,39]. The increase in portal vein flow in response to tezosentan implies an increased blood flow to the liver, but since we did not measure hepatic artery flow, we could not calculate the total blood flow to the liver.…”

Role of Kupffer Cells in Vascular Stress Genes During Trauma and Sepsis

“…Several lines of evidence suggest that the disruption of microvascular blood flow during sepsis might contribute to the subsequent development of MODS [3]. Liver microcirculation is normally maintained under the fine balance of vasoconstrictors and vasodilators, of which endothelin-1 (ET-1), nitric oxide (NO), and carbon monoxide (CO) have been reported to be the prominent vasomediators [4].…”