Involvement of calmodulin-calcium complex in regulation of O2 uptake in regions of the liver lobule

Abstract

In livers from phenobarbital sodium-treated rats, O2 uptake was two- to three-fold higher in periportal than in pericentral regions during perfusions in the anterograde direction confirming previous studies. The purpose of this study is to evaluate the role of calmodulin in the regulation of local rates of O2 uptake. O2 uptake was inhibited up to 80% in a dose-dependent fashion by the calmodulin inhibitor, W-7 (I0.5 = 50-60 microM). In isolated mitochondria, however, W-7 had minimal effects on state 3 and 4 rates of O2 uptake. Moreover, fructose increased O2 uptake in perfused liver to a similar extent in the presence and absence of W-7, indicating that a direct effect of W-7 on mitochondria in the perfused liver can be ruled out. In perfusions in the anterograde direction, W-7 (100 microM) decreased O2 uptake from 129 to 45 mumol . g-1 . h-1 in upstream periportal regions of the liver lobule and from 47 to 36 mumol . g-1 . h-1 in downstream pericentral areas. When perfusion was in retrograde direction, however, O2 uptake was twofold higher in upstream pericentral areas. Under these conditions, W-7 decreased O2 uptake from 160 to 59 mumol . g-1 . h-1 in upstream pericentral areas and from 58 to 43 mumol . g-1 . h-1 in downstream periportal regions. Thus W-7 decreased O2 uptake predominantly in upstream regions of liver lobule irrespective of the direction of flow. Increases in O2 uptake caused by epinephrine (0.1 microM) and angiotensin II (5 nM), hormones that increase intracellular Ca2+, were blocked totally by W-7.(ABSTRACT TRUNCATED AT 250 WORDS)