Effects of retrograde flow on measured blood volume, Disse space, intracellular water space and drug extraction in the perfused rat liver: characterization by the multiple indicator dilution technique.
Previous rat liver perfusion studies had shown a preferential derecruitment of downstream (phenacetin O-de-ethylation) in relation to upstream (acetaminophen sulfation) hepatocyte activities with reductions in prograde (normal) flow, with substrates entering from the portal vein and exiting the hepatic vein. The reduction in metabolic activities was found associated with a reduction in accessible intracellular water space (Pang et al., J. Pharmacokinet. Biopharm. 16: 595, 1988). In the present studies, we investigated the changes in metabolic activities of the liver and its accessible spaces during retrograde flow (substrates entering from the hepatic vein and exiting the portal vein), an approach used to probe zonal heterogeneity in the liver. The multiple indicator dilution technique was used to gain information concerning the accessible sinusoidal blood volume, Disse space, and the intracellular water space; once-through perfusion with tracer [3H]acetaminophen and [14C]phenacetin was performed simultaneously within the same liver, to estimate metabolic activities at the periportal and perihepatic venous regions of the liver, respectively, at the designated flows. The estimated sinusoidal blood volume, total albumin and sucrose distribution spaces, the Disse space and the accessible albumin and sucrose Disse spaces showed weak but positive correlations with retrograde perfusate flow rate. The values were substantially greater than those for rat livers perfused with normal (prograde) flows, suggesting an increase in the vascular space and accessible Disse space of the liver during retrograde flow. The total water and accessible intracellular water spaces also showed weak but positive correlations with retrograde perfusate flow, and the average intracellular water space (which is also accessed by the substrates) at both retrograde flows of 8 and 12 ml/min was 0.52 +/- 0.08 and 0.55 +/- 0.08 ml/g liver, respectively, values that were not statistically different. When the intracellular water space was plotted vs. water flow rate (ml water/g liver), a weakly positive correlation was again found, suggesting that over the flow range, the accessible intracellular water space decreased in a very gradual and linear fashion with a reduction in water flow rate. When the estimated intracellular water space for retrograde flow was compared with values obtained for the same flow rate in a prograde fashion, slightly lower values were obtained. After consideration of the effect of the distended vascular and interstitial spaces on the weights of the liver, the values obtained for retrograde and prograde flow rates were closely similar. In both cases, it appeared that with reduction in flow, the accessible intracellular water spaces were reduced, regardless of the flow direction.(ABSTRACT TRUNCATED AT 400 WORDS)
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
N
N
Xu
A
A
Chow
C A
CA
Goresky
K S
KS
Pang
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001810:Blood Volume; D001834:Body Water / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D010615:Phenacetin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000032:analysis; D013395:Sucrose / Q000097:blood
D012709:Serum Albumin; D000082:Acetaminophen; D013395:Sucrose; D010615:Phenacetin