The hepatic uptake of a hydrophilic, cationic linear peptide with renin inhibitory activity [5(4-amino-piperidyl-1-carbonyl)-L-2,6[3H]phenyl-alanyl-beta-alanyl-(4S- amino-3S-hydroxy-5-cyclohexyl)-pentan-carbonyl-L-isoleucyl-amin ome thyl-4-amino-2-methyl-pyrimidine-citrat] (code number EMD 56133; EMD, E. Merck, Darmstadt) was investigated in isolated rat hepatocytes. EMD 56133 was taken up by isolated rat liver cells in a time-, concentration-, energy- and temperature-dependent manner. The uptake was a combination of diffusion and a carrier-mediated process. EMD 56133 was accumulated 4.5-fold in liver cells. Eighty-three per cent of the accumulated peptide was found in the cytosol, not bound to membrane proteins. Seventeen per cent was associated with membrane proteins after cell fractionation and centrifugation at 100,000 g. The permeability coefficient of the non-saturable uptake of EMD 56133 was P = 1.973 x 10(-6) cm/sec. The kinetic constants for the carrier-mediated transport are Km = 92 microM and Vmax = 128 pmol/mg x min. Various substrate analogs inhibited the uptake of EMD 56133. AS-30D ascites hepatoma cells and Reuber hepatoma cells did not accumulate EMD 56133. The absence of oxygen or a decreased cellular ATP content blocked the hepatocellular uptake of the renin inhibitor. Temperatures above 20 degrees increased the transport; the activation energy was determined to be Aapp = 41 kJ/mol. The apparently active uptake of EMD 56133 was not sodium dependent. In contrast, the membrane potential might be a driving force for the transport of the positively charged EMD 56133.

01 Feb 1993·Biochemical Pharmacology

Hepatocellular uptake of peptides—II

Article

Author: Kornelia Ziegler ; Agnes Seeberger

To define the endogenous transport system responsible for the hepatocellular uptake of hydrophilic linear peptides, interactions between the cationic renin-inhibitor, [5(4-amino-piperidyl-1-carbonyl-L-2,6[3H]phenyl-alanyl-beta-alanyl(4S- amino-3S-hydroxy-5-cyclo-hexyl)-pentan-carbonyl-L-isoleucyl-ami nom ethyl-4-amino-2-methyl-pyrimidine-citrat] (code number EMD 56133; EMD, E. Merck, Darmstadt) and substrates of endogenous transport systems of liver cells were studied in isolated rat hepatocytes. EMD 56133 competitively inhibited the uptake of ouabain (Ki = 75 microM) and vice versa (Ki = 200 microM). In contrast, the sodium-dependent as well as the sodium-independent uptake of cholate and the total uptake of taurocholate were non-competitively blocked, whereas EMD 56133 decreased the uptake of the cyclosomatostatin 008 in an uncompetitive manner. EMD 56133 did not interfere with transport systems for monovalent organic cations, amino acids and long chain fatty acids. The uptake of rifampicin, however, was increased in the presence of EMD 56133. The transport of EMD 56133 was non-competitively inhibited by cholate (Ki = 126 microM) and taurocholate (Ki = 44 microM), and uncompetitively inhibited by the linear peptide EMD 51921. In contrast, the uncharged compound ouabain (Ki = 200 microM) and the bivalent organic cation d-tubocurarine (Ki = 370 microM) competitively inhibited the uptake of the renin inhibitor. Several substrates of other endogenous transport systems (e.g. bilirubin, cyclopeptides, monovalent cations, dipeptides, amino acids, fatty acids, hexoses) did not interfere with the transport of EMD 56133. Our results suggest that transport systems for bivalent organic cations or uncharged compounds (ouabain) are able to eliminate the linear hydrophilic peptide tested.

01 Jan 1993·Clinical and Experimental HypertensionQ4 · MEDICINE

Renin and Renin Inhibition in Anephric Man

Q4 · MEDICINE

Article

Author: Paul A. Abraham ; Kevin L. Smith ; John A. Opsahl ; Stephen A. Katz ; Robert D. Murray

Renin activity appears to be present in low concentrations in the plasma of anephric humans but could be artifactual secondary to inadvertent activation of prorenin during specimen collection and handling or from a renin-like enzyme. We studied the effects of specimen collection, storage, different assay conditions, trypsin activation, and the renin inhibitor EMD 56133 (E Merck, Darmstadt) on plasma renin activity (PRA) in anephric man. PRA was detectable in all seven bilaterally nephrectomized (BNX) patients (0.2 +/- 0.1 ng AI/ml/hr, range 0.1-0.7) but was significantly lower than normals (2.4 +/- 0.3 ng AI/ml/hr, range 1.5-3.1, p = 0.001). PRA was not different in BNX whether blood samples were collected on ice or at room temperature and assayed immediately or whether samples were frozen and assayed several days later. Prolonged cold storage of samples and five freeze-thaw cycles over six to seven months did not significantly increase PRA in normals or anephrics. However, deliberate repeated freezing and thawing over the period of a single day increased PRA 4.1-fold in BNX and 1.6-fold in normals. Renin-like activity was also detected in BNX individuals using renin concentration determinations with either excess human or sheep angiotensinogen. The inhibition of renin activity (IC-50% = 3.16 x 10(-9) molar) by EMD 56133 was not different between BNX and normals. Thus, active renin is present in the plasma of anephric humans and does not result from the inadvertent activation of prorenin due to sample handling. Although the source of PRA in BNX is unknown, the enzyme appears functionally normal as evidenced by the dose-response to a single renin inhibitor.

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