Evidence for phosphoramidon-sensitive cleavage of big endothelin-1 involved in endothelin-stimulated hepatic glucose production.
Endothelin-1 (ET-1) is known to stimulate glycogenolysis in perfused rat livers and isolated rat hepatocytes. To determine the potential action of endothelin's precursor, big endothelin-1 (big ET-1), isolated rat livers were perfused with big ET-1 in a non-recirculating system. Thereby, big ET-1 (10 nM) induced a maximally three-fold increase (P < 0.01 vs. basal values) in hepatic glucose production at 60 min, which was almost completely abolished by concomitant infusion of 50 microM phosphoramidon, a sensitive inhibitor of the enzymatic cleavage of big ET-1 to ET-1. The corresponding incremental release of glucose by big ET-1 was 20.9-fold higher in the absence of phosphoramidon than in its presence (P < 0.01). In contrast, phosphoramidon did not inhibit hepatic glucose production induced by ET-1 (1 nM), glucagon (1 nM), and phenylephrine (5 microM). Glycogenolytic responses to 1 nM ET-1 (P < 0.01), but not to 1 nM glucagon (n.s.) were blocked by indomethacin (100 microM), indicating that prostaglandin release by non-parenchymal cells is at least in part involved in the hepatic ET-1 action. In conclusion, big ET-1 induces hepatic glucose release, which is suggested to depend on intrahepatic conversion of big ET-1 to ET-1 by a phosphoramidon-sensitive pathway.
Roden
M
M
Institute of Medical Statistics, University of Vienna, Austria.
Prskavec
M
M
Fürnsinn
C
C
Schneider
B
B
Waldhäusl
W
W
Vierhapper
H
H
D000818:Animals; D019332:Endothelin-1; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D010656:Phenylephrine; D005934:Glucagon; D015260:Neprilysin; D005947:Glucose; C008890:phosphoramidon; D007213:Indomethacin