Role of Calcium in Regulation of Hepatic Oxygen Uptake

Abstract

In recent studies, we employed miniature O2 electrodes placed on periportal and pericentral regions of the liver lobule to measure local rates of oxygen uptake. In the perfused liver, O2 uptake was 2- to 3-fold higher in periportal (137 ± 8 μmol/g/h; O2 concentration = 478 ± 37 μM) than in pericentral regions (59 ± 5 μmol/g/h; O2 concentration = 263 ± 25 μM) of the liver lobule. O2 uptake was also greater in periportal than pericentral regions of the liver lobule at physiological O2 tensions in situ. In perfusions in the natural anterograde direction, oxygen uptake was dependent on oxygen at oxygen concentrations considerably higher than levels that caused reduction of NADH. It is well known that the Km of mitochondrial cytochrome oxidase for O2 is very low (less than 1 μM); however, rates of O2 uptake in the whole organ declined to about one-quarter of maximal values when O2 concentration in the inflow perfusate was diminished under conditions before hypoxia reflected by reduction of NAD+ could be detected. Maximal rates of O2 uptake were dependent on O2 tensions greater than 200 μM. Based on studies with inhibitors of oxidative phosphorylation, it was concluded that O2 uptake in both regions of the liver lobule was dependent largely on mitochondrial electron transport. The regional distribution of oxygen uptake was reversed when perfusion was in the retrograde direction, resulting in rates of O2 uptake 2- to 3-fold higher in pericentral than in periportal regions of the liver lobule. Further, the lower rates of O2 uptake observed in downstream regions of the liver lobule were not due to hypoxia since the ATP content and the ATP:ADP ratio were similar in microdissected samples from periportal and pericentral regions. On the other hand, agents which increased intracellular free calcium, such as epinephrine (0.1 μM), elevated rates of O2 uptake predominantly in downstream regions of the liver lobule irrespective of the direction of flow in perfused liver. In contrast, W-7, an inhibitor of calmodulin, diminished rates of O2 uptake predominantly in upstream regions of the liver lobule irrespective of the direction of flow. Thus, in addition to regulation by the supply of ADP, it is concluded that the calcium-calmodulin complex is involved in the regulation of local rates of O2 uptake in perfused liver.