Sensitivity of propranolol elimination to hypoxia in the isolated perfused rat liver preparation

1. The relationship between the hepatic elimination of propranolol and hepatic oxygen delivery was examined in the single-pass isolated perfused rat liver preparation. Varying rates of oxygen delivery were produced (1.35-8.10 mumol/min per g liver) by equilibrating the perfusate with O2/N2 mixtures. 2. In two experiments, in which the rate of oxygen delivery was increased or decreased within the hypoxic range (< 4-5 mumol/min per g liver) every 5 min for 120 min, propranolol clearance responded very rapidly in the same direction as the change in oxygen delivery. 3. In five experiments, propranolol clearance, measured at steady state during an initial 30 min normoxia phase and three subsequent 30 min hypoxia phases (oxygen delivery in the range 1.35-5.89 mumol/min per g liver), was linearly related to hepatic oxygen delivery and consumption (r = 0.92 +/- 0.07). 4. These data, combined with those from six further experiments that used one normoxia phase followed by one hypoxia phase, showed that there was a threshold for oxygen delivery of about 6 mumol/min per g liver, below which propranolol clearance decreased with decreasing oxygenation. 5. This study shows that in the intact liver propranolol elimination is very sensitive to hepatic oxygen supply, with impairment in clearance occurring at the lower limit of what is considered normal hepatic oxygenation in the rat.