Hemorrhagic shock primes the hepatic portal circulation for the vasoconstrictive effects of endothelin-1

To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ETA receptor agonist ET-1 and of the selective ETB receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 × 10−9 M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 × 10−9 M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ETBreceptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.

Hepatic oxygen metabolism in porcine endotoxemia: the effect of nitric oxide synthase inhibition

The role of endotoxin (lipopolysaccharide, LPS) and nitric oxide in hepatic oxygen metabolism was investigated in 36 pigs receiving 1) LPS (1.7 μg ⋅ kg−1 ⋅ h−1) for 7 h and N G-nitro-l-arginine methyl ester (l-NAME; 25 mg/kg) after 3 h, 2) LPS, 3) NaCl andl-NAME, and 4) NaCl. Infusion of LPS reduced hepatic oxygen delivery (Do 2H) from 60 ± 4 to 30 ± 5 ml/min ( P < 0.05) and increased the oxygen extraction ratio from 0.29 ± 0.07 to 0.68 ± 0.04 after 3 h ( P < 0.05). Hepatic oxygen consumption (V˙o 2H) was maintained (18 ± 4 and 21 ± 4 ml/min, change not significant), but acidosis developed. Administration ofl-NAME during endotoxemia caused further reduction of Do 2H from 30 ± 3 to 13 ± 2 ml/min ( P < 0.05) and increased hepatic oxygen extraction ratio from 0.46 ± 0.04 to 0.80 ± 0.03 ( P< 0.05). There was a decrease inV˙o 2H from 13 ± 2 to 9 ± 2 ml/min that did not reach statistical significance, probably representing a type II error. Acidosis was aggravated. Administration of l-NAME in the absence of endotoxin also increased the hepatic oxygen extraction ratio, but no acidosis developed. In a different experiment, liver blood flow was mechanically reduced in the presence and absence of endotoxin, comparable to the flow reductions caused byl-NAME. The increase in hepatic oxygen extraction ratio (0.34) and maximum hepatic oxygen extraction ratio (∼0.90) was similar whether Do 2H was reduced by occlusion or byl-NAME. We concluded thatl-NAME has detrimental circulatory effects in this model. However, neither endotoxin norl-NAME seemed to prevent the ability of the still circulated parts of the liver to increase hepatic oxygen extraction ratio to almost maximum when oxygen delivery was reduced. The effect of l-NAME on oxygen transport thus seems to be caused by a reduction in Do 2H rather than by alterations in oxygen extraction capabilities.

Dopamine and hepatic oxygen supply – demand relationship

The present study examined the effect of small, vasodilating doses of dopamine on the hepatic oxygen supply – uptake ratio. Thirteen miniature pigs weighing 18–27 kg were studied under sodium pentobarbital anesthesia. Hepatic arterial and portal blood flows were measured. Oxygen content in arterial, portal, and hepatic venous blood was determined. Dopamine was infused in doses of 5, 10, and 15 μg∙kg−1∙min−1. Dopamine infusion was associated with a dose-related increase in hepatic oxygen uptake and a dose-independent increase in hepatic oxygen delivery with a maximal increase (30%) in the hepatic oxygen delivery at 10 μg∙kg−1∙min−1. The hepatic oxygen delivery–uptake ratio remained unchanged during dopamine infusion in doses of 5 and 10 μg∙kg−1∙min−1 and significantly decreased during the dose of 15 μg∙kg−1∙min−1. The study demonstrated that an increase in cardiac output and hepatic oxygen delivery during dopamine administration was not associated with an improvement in hepatic oxygen supply – demand relationship since hepatic oxygen uptake also increased.Key words: dopamine, hepatic blood flow, hepatic oxygenation.

Hypothermia, hepatic oxygen supply-demand, and ischemia-reperfusion injury in pigs

We examined the effects of two degrees of hypothermia on hepatic oxygen delivery and uptake, hepatic lactate uptake as a marker of hepatic function, and the effect of hypothermia on ischemia-reperfusion injury in the liver in miniature pigs (n = 18, 21-30 kg body wt). Hepatic arterial and portal venous blood flows were measured while hepatic oxygen delivery was progressively decreased without venous congestion in the preportal area. With decreases in hepatic blood and oxygen supply, oxygen extraction gradually increased from 50 to 90% in the normothermic group and from 25 to 70 and 84% in the hypothermic (30. and 34 degrees C, respectively) groups. The values of critical hepatic oxygen delivery were between 7.3 and 11.9 ml O2.min-1.100 g-1 without significant differences among the groups. During reperfusion after ischemic insult, hepatic oxygen uptake returned to base-line values in both hypothermic groups but remained substantially below base-line values in normothermic groups of animals. Hepatic enzyme concentrations (lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, and alcohol dehydrogenase) were substantially increased (up to 30-fold) in normothermic animals, but the concentrations did not increase in either of the hypothermic groups. These results demonstrated that hypothermia per se does not affect hepatic oxygen delivery but decreases hepatic oxygen demand and uptake, provides an effective protection from hepatic oxygen deprivation, and lessens reperfusion injury.