title: Intrarenal octreotide treatment prevents sodium retention in liver cirrhotic rats: evidence for direct effects within the thick ascending limb of Henle's loop.
abstract: We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F, and Petersen JS. Hepatology 29: 1387-1395, 1999). In the present study, we tested the hypothesis that octreotide has a direct effect on renal tubular function. Rats (CBL or Sham-CBL) were intrarenally treated with low-dose octreotide in a long-acting release formulation, which had no systemic actions (100 microg/kg body wt as a single dose). Rats receiving low-dose octreotide (sc) were used as controls. The rats were chronically instrumented, and renal function was examined 4 wk after CBL or Sham-CBL. Intrarenal octreotide administration (IROA) prevented sodium retention in CBL rats without changes in renal plasma flow, glomerular filtration rate, or circulating levels of aldosterone and vasopressin. Renal clearance studies revealed that IROA normalized the increased natriuretic efficacy of furosemide found in CBL rats. Furthermore, IROA protected against the development of hypertrophy of the inner stripe of the outer medulla and thereby the increased the volume of thick ascending limb of Henle's loop (TAL) epithelium found in CBL rats. Finally, Western blot analyses of outer medullary homogenates showed increased abundance of the furosemide-sensitive Na-K-2Cl (NKCC2) cotransporter. IROA did not affect the abundance of NCKK2 within the outer medulla. Together with the histological findings, these results indicate that IROA reduces the total number of NKCC2 within the outer medulla. In conclusion, the results indicate a direct intrarenal effect of octreotide on TAL function and morphology in cirrhotic rats.
authors.affiliation: Department of Pharmacology, The Panum Institute, University of Copenhagen, 3 Blegdamsvej, Bldg. 18.5, DK-2200 Copenhagen N, Denmark. fitj@farmakol.ku.dk
authors.forename: Thomas E N
authors.initials: TE
authors.lastname: Jonassen
authors.forename: Sten
authors.initials: S
authors.lastname: Christensen
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.forename: Jørgen Søberg
authors.initials: JS
authors.lastname: Petersen
mesh_terms: D000818:Animals; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy*; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008138:Loop of Henle / Q000187:drug effects* / Q000473:pathology; D015282:Octreotide / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
chemical_list: D005665:Furosemide; D012964:Sodium; D015282:Octreotide