Endothelin‐induced vasoconstriction in isolated perfused liver preparations from normal and cirrhotic rats

Abstract

Isolated, perfused rat liver preparations (IPRL), obtained from rats with carbon tetrachloride-induced cirrhosis and normal controls, were used to investigate responses to the vasoactive peptide endothelin-1 (ET-1). The mean perfusion resistance (R) of cirrhotic IPRL was significantly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mmHg/mL per min per g; P < 0.01). Both control and cirrhotic IPRL demonstrated a concentration-related increase in resistance (delta R) in response to ET-1, with a minimum effective concentration of approximately 3 x 10(-11) mol/L. The EC50 (-log of the 50% effective concentration) was not significantly different between cirrhotic and control IPRL (8.48 +/- 0.19 and 8.79 +/- 0.11, respectively); however, the maximum response to ET-1 was significantly greater in cirrhotic preparations (R: 10.4 +/- 2.2 vs 4.4 +/- 0.5 mmHg/mL per min per g, P < 0.01; DR, 7.8 +/- 2.1 vs 2.8 +/- 0.4 mmHg/mL per min per g, P < 0.01). Following maximal stimulation by ET-1, the mean portal-hepatic venous pressure gradient at a physiological flow rate of 1 mL/min per g was approximately 90% greater across cirrhotic IPRL than that across normal IPRL (11.2 +/- 2.0 vs 5.9 +/- 0.9 mmHg, respectively; P < 0.05). These results support the hypothesis that endogenously released ET-1 has a significant influence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.

Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

“…2 This dynamic component of hepatic vascular resistance is believed to be the consequence of an imbalance between the vasodilator/vasoconstrictor forces that regulate hepatic vascular tone. 1 In addition, the hepatic vascular resistance of cirrhotic livers exhibits a hyperresponse to several vasoconstrictors, such as endothelin 1, 3 norepinephrine, 4 or leukotriene D 4 . 5 Nitric oxide blunts the response of the hepatic vascular bed to several vasoconstrictors, 6 and its production is decreased in the cirrhotic liver.…”

Role of Sodium Nitroprusside in the Improvement of Rat Liver Preservation in University of Wisconsin Solution: A Study in the Isolated Perfused Liver Model

“…Other authors [27] using the isolated perfused rat liver, have shown that both ET-1 and ET-3 increase resistance to flow through the portal vascular bed of normal livers and that the vasoconstrictor action of ET is effectively reversed by NPNa.…”

Endothelin-Induced Contraction of the Portal Vein in Cirrhosis

“…In experimental systems including the present one, the ET concentration at which ET induces vasoconstriction of portal/mesenteric veins ranges from 10 -9 to 10 -7 M [21,40]. Moreover, arteries show also in vitro a vasoconstriction within this concentration range [39].…”

“…On the other hand, other in vivo studies clearly indicate the involvement of ET in portal hypertension [20,45,46]. Especially, one study examining the effect of ET-1 in isolated perfused livers has found that ET-1 causes a significant increase of portal vascular resistance in cirrhotic rat livers [21]. Even vascular hyperresponsiveness of mesenteric vessels to ET was observed under in vitro conditions [47].…”

“…There is strong evidence that the net splanchnic release of ETs is the reason for elevated plasma concentrations [11,13]. Experimental and clinical studies have demonstrated that exogenous ET-1 causes portal hypertension [19][20][21], and it has therefore been suggested that ET plays an important role in the pathophysiology of portal hypertension [22]. In this context, the ETinduced contraction of hepatic stellate cells (Ito, endothelial cells) has been proposed to be mainly responsible for the development of portal hypertension [23].…”