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.)

The authors examined the natriuretic efficiency of furosemide in rats with cirrhosis induced by carbon tetrachloride (CCl 4 ). Rats were treated for 17 weeks with intraperitoneal injections of CCl 4 in groundnut oil twice a week throughout the study. Control rats were treated with vehicle (groundnut oil). Studies in metabolic cages showed that sodium retention was present from week 14. Renal clearance experiments were performed in chronically, instrumented conscious rats at the end of week 14 and at the termination of the study (end week 16) when ascites and hyponatremia were present. After 14 weeks, cirrhotic rats had sodium retention along with increased renal plasma flow, normal GFR, normal renal lithium handling, and a significantly increased diuretic (؉41% vs. control) and natriuretic (؉56% vs. control) response to a test dose furosemide (7.5 mg/kg b.w., intravenously). The natriuretic efficiency of furosemide, i.e., the natriuresis expressed relative to the furosemide excretion rate (⌬U Na V/U FUR V) was increased by 51% versus control. After 17 weeks, ascites and hyponatremia had developed, and significant decreases in renal plasma flow (؊33%), GFR (؊30%), and fractional lithium excretion (؊44%) were observed. At this stage urinary recovery of furosemide was significantly decreased and the diuretic (؊27% vs. Control) and natriuretic (؊38% vs. control) responses to furosemide were significantly impaired. However, the increased natriuretic efficiency of furosemide was still present (؉34% vs. control). Together these results suggest that increased sodium reabsoprtion in the thick ascending limb of Henle's loop is involved in the renal sodium retention in cirrhosis in rats that eventually results in decompensation with the

Abstrucr; Acute intracerebroventricular administration of the antihyperglycaemic agent metformin (0.25-1 mg) elicits sympathoinhibitory responses in spontaneously hypertensive rats. However, cardiovascular actions of chronic intracerebroventricular metformin administration are unknown. To define the dose-response relationship during chronic intracerebroventricular metformin administration, mean arterial pressure, heart rate, and locomotor activity were measured continuously by radiotelemetry in 40 normotensive rats. After a 10 day control period, an intracerebroventricular cannula was implanted and connected to an osmotic minipump which delivered metformin in the following doses: 0 [saline], 0.0 I. 0.1 I , and 10 mgiday. LD5" was 1.5 mg/day. Metformin. 1 mgiday attenuated the nocturnal, physiological increase in mean arterial pressure (-7.32 I .6'%1 versus before metformin). produced behavioural changes and tended to increase locomotor activity. Lower doses of intracerebroventricular metformin (0.1 and 0.01 mgiday) did not affect mean arterial pressure, heart rate or locomotor activity. In conclusion. chronic intracerebroventricular administration of high dose metformin ( I .O mgiday) attenuates the nocturnal. physiological increase in mean arterial pressure. These findings are compatible with a toxic. sympathoinhibitory action of high doses of metformin intracerebroventricularly.Metformin is an antihyperglycaemic agent used for treatment of type 11 diabetes niellitus. In contrast to antihyperglycaemic drugs of the sulphonylurea class, metformin has favourable effects on several cardiovascular risk factors. Thus, metformin decreases plasma insulin levels and prevents weight gain (United Kingdom Prospective Diabetes Study Group 1995). In patients with hyperlipidemia, metformin decreases plasma levels of total cholesterol, lowdensity lipoprotein, and triglycerides and several studies have demonstrated that metformin increases the fibrinolytic activity in plasma (United Kingdom Prospective Diabetes Study Group 1995;Campbell et al. 1987;Chan et al. 1993 velopment of arterial hypertension. However, this argument is only valid provided that metformin and thiazolidinedione derivatives do not lower arterial pressure by other mechanisms than changes in insulin sensitivity. We have previously demonstrated that acute intravenous and intracerebroventricular administration of metformin elicits a marked sympathoinhibitory response in spontaneously hypertensive rats which could contribute substantially to the antihypertensive action of metformin (Petersen & DiBona 1996 Petersen et ul. 1997; Muntzel et al. 1997). However, whether a central action could be involved in the long-term antihypertensive action of metformin is unknown. Thus, the aim of the present study was to evaluate the long-term actions of intracerebroventricular metformin administration and to define the possible therapeutic and toxic dose ranges during chronic intracerebroventricular metformin administration in rats. To examine the dose-response relationship on ...