We examined the effect of a new long-acting release formula (LAR) of the somatostatin analogue, octreotide, on development of sodium retention and functional and structural changes in the thick ascending limb of Henle's loop (TAL) in rats with cirrhosis induced by common bile duct ligation (CBL). CBL and sham-operated control rats were treated with octreotide-LAR (10 mg/kg body weight subcutaneously, as a single dose) or vehicle at the time of CBL or sham-CBL. The rats were instrumented with chronic catheters, and sodium balance and renal function were examined 4 weeks after CBL or sham operation. Octreotide-LAR treatment significantly inhibited sodium retention in CBL rats and prevented renal vasodilatation without changes in glomerular filtration rate (GFR). The natriuretic response to a test dose of furosemide (7.5 mg/kg body weight intravenously) was significantly increased in CBL rats, and when expressed in terms of natriuretic efficiency (mmol Na/mg furosemide in urine), the natriuretic response was increased by 57% relative to sham-operated controls. Stereological examination of kidneys demonstrated a 53% increase in the volume of the inner stripe of the outer medulla and a 108% increase in the volume of TAL epithelium in cirrhotic rats relative to controls. The increased natriuretic efficiency of furosemide as well as the hypertrophy of the inner stripe and the TAL in this renal zone were absent in CBL rats treated with octreotide-LAR. These results suggest that octreotide-LAR treatment inhibits sodium retention in cirrhotic rats, partly by inhibition of increased furosemidesensitive sodium reabsorption in the TAL. (HEPATOLOGY 1999;29:1387-1395.)
Cirrhosis is a chronic disease characterized by marked changes in systemic and renal hemodynamics and the renal handling of Na and water. Cirrhotic patients and experimental animals gradually develop Na-retention, which eventually results in the formation of edema and ascites. The mechanisms that initiate Na-retention during cirrhosis are not known. Peripheral vasodilation precedes Na-retention in cirrhotic liver disease. Therefore, it has been proposed that sodium retention is a secondary event to systemic vasodilation. Long-term treatment with the nonspecific nitrous oxide synthase inhibitor, N G -nitro-L-arginine methyl ester, reverses systemic vasodilation and ameliorates Na-retention in rats with carbon tetrachloride-induced cirrhosis. 2 Similarly, chronic treatment with the somatostatin analogue, octreotide, reverses the systemic vasodilatation and ameliorates renal Na-retention in the same animal model of cirrhosis. 3 However, the mechanism by which systemic vasodilation causes sodium retention is unknown, but it seems to be mediated by an increased tubular Na-reabsorption, because the glomerular filtration rate (GFR) is unaltered at this stage of the disease. Recently, we investigated renal tubular sodium handling in rats with cirrhosis induced by common bile duct ligation (CBL). The rats had Na-retention, but no signs of ascites. During these conditions, the cirrhotic rats had an increased natriuretic response to furosemide and an increased volume of the thick ascending limb of Henle' s loop (TAL) epithelium in the inner stripe of the outer medulla. These findings suggest that increased Na-reabsorption in the TAL may be involved in the early sodium retention that precedes ascites formation in rats with cirrhosis.
The mechanism by which octreotide reverses the systemic vasodilation and ameliorates sodium retention in rats with cirrhosis is unknown. Sieber et al. 10 found that octreotide did not have a direct action on the endothelium-derived nitrous oxide release in portal hypertensive rats. Therefore, these authors and others have suggested that octreotide treatment modulates the release of vasoactive peptides like glucagon and insulin from the gastrointestinal system during conditions with portal hypertension However, the renal tubular effects of chronic octreotide treatment in cirrhotic liver disease are unknown.
The aim of this study was to examine the long-term effects of octreotide treatment on sodium balance and on the functional and the structural changes in the TAL in rats with cirrhosis induced by CBL.