Clearance of Immunoreactive Somatostatin by Perfused Rat Liver

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Abstract
Other investigators have demonstrated that concentrations of immunoreactive somatostatin (IRS) are higher in blood from the hepatic portal vein or its tributaries than in blood from the hepatic or peripheral systemic veins of man and animals. This suggests that there is hepatic extraction of IRS from the portal system in vivo. In the rat, portal vein plasma IRS is reported to be heterogeneous and to contain, in part, a 1,600 mol wt form of IRS which is immunochemically similar to synthetic somatostatin and not significantly bound to high molecular weight plasma protein. Our study was undertaken to determine directly whether unbound synthetic cyclic somatostatin was cleared by the rat liver perfused through the hepatic portal vein in vitro with a recirculating, plasma-free, erythrocyte-containing perfusate. At 37°C and pH 7.40, perfusate IRS, at initial concentrations (1,728 pg/ml) within the range previously reported in rat portal venous blood, was removed by the liver at a rate commensurate with first-order kinetics. Hepatic clearance was 0.84±0.04 ml/min per g postperfusion wet weight (SE). Hepatic extraction was 36±2%, and t½ was 20.0±1.3 min. Recovery of IRS from the perfusate without the liver was >85%, excluding significant degradation by the medium. Clearance, extraction, and t½ of IRS were not changed by an unphysiologic IRS concentration (621,500 pg/ml), or by pharmacologic concentrations of insulin (8.2 μM) or glucagon (2.9 μM). The t½ was prolonged significantly to 28.2±1.9 and 45.6±4.7 min during perfusions at liver temperatures of 25° and 16°C, respectively. At 37°C, the t½ was also significantly increased to 28.7±3.2 and 24.2±1.1 min at perfusate pH 7.06 and 6.78, respectively. These studies indicate that the rat liver clears unbound IRS from the perfusate by a first-order kinetic process that is (a) unsaturable at pharmacologic concentrations, (b) temperature-sensitive and, to a lesser extent, influenced by lowered pH, and (c) not affected by insulin and glucagon. The liver would appear to play an important role in the metabolism of the 1,600 mol wt form of somatostatin. Clearance of endogenous IRS by the liver should be considered in the interpretation of IRS concentrations in the peripheral systemic veins.