Regulation of hepatic blood flow during resuscitation from hemorrhagic shock: role of NO and endothelins

Abstract

We determined the role of nitric oxide (NO) and endothelins (ETs) in the regulation of hepatic blood flow during resuscitation from hemorrhagic shock (HS) in anesthetized rats. Volume resuscitation restored systemic hemodynamics and increased hepatic arterial and portal venous flow above baseline in the vehicle group. Presence of N omega-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) during resuscitation increased systemic vascular resistance (SVR) above baseline, prevented the restoration of hepatic arterial flow, and abolished portal hyperemia. Although the ETA+B-receptor antagonist bosentan (10 mg/kg) did not alter the systemic hemodynamic response, it abolished the hepatic arterial and portal hyperemia. The ETA-receptor antagonist BQ-610 (150 micrograms/kg) reduced SVR below baseline, allowed hepatic arterial hyperemia to occur, and further enhanced the portal venous hyperemia. This indicates that 1) NO reduces SVR and acts to preserve hepatic blood flow during resuscitation from HS; 2) ETA-receptor-mediated vasoconstriction counteracts the systemic and portal hemodynamic effects of NO; and 3) simultaneous ETB-receptor stimulation enhances blood flow to the liver and may serve to modulate the ETA-receptor-mediated vasoconstrictive effects of ETs.

Role of nitric oxide in inflammation and tissue injury during endotoxemia and hemorrhagic shock.

“…Nonspecific 'NO blockade increased shock-induced hepatic injury, an effect that was reversible with L-arginine (37). A recently published study reports that the presence of an NOS inhibitor, L-NAME, during resuscitation from hemorrhage prevented the restoration of hepatic arterial blood flow, suggesting a role for 'NOmediated vasodilatation in preventing hepatic ischemia during HS (38). In addition, the administration of 'NO donors has been beneficial in models of traumatic shock, hemorrhagic shock, and mesenteric ischemia-reperfusion injury (39).…”

“…Although NOS inhibition has improved hemodynamics in several models of HS (35,36), various examples of organ dysfunction have also been seen with their use (37,38). It may be that better understanding and characterization of the pharmacokinetics and selectivity of NOS inhibitors is needed prior to their use in HS.…”

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

“…In hepatic ischemia and reperfusion there appears to be an imbalance of vasodilator factors, like nitric oxide, and vasoconstrictor factors, like ET-1, leading to a decreased blood flow to the liver during reperfusion (58 tissue and endothelium of the portal bed (25) and its production is increased several-fold after ischemia (34). Accordingly, microvascular perfusion failures after liver transplantation could be attenuated by either combined ET A/B -receptor or selective ET A -receptor antagonists (26).…”

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

“…Furthermore, eNOS-derived NO production is altered in vascular diseases in the liver (13,19). For example, in liver cirrhosis and portal hypertension, a syndrome characterized by increased intrahepatic vasoconstrictive responses and impaired vasodilation, a deficit in hepatic NO production, has been demonstrated (8,16,22,23).…”