Negative modulation of nitric oxide production by neurotensin as a putative mechanism of the diuretic action of SR 48692 in rats

Abstract

*Sano® Recherche, 195 route d'Espagne, 31036 Toulouse, and {32/34 rue Marbeuf, 75374 Paris, France 1 We investigated the e ect of the non-peptide neurotensin (NT) antagonist SR 48692 on renal function in rats and the involvement of nitric oxide (NO) in the diuretic action of this compound. 2 In fed animals, SR 48692 dose-dependently (0.5 to 12.5 mg kg 71 , p.o., 0.03 to 1 mg kg 71 , i.p. and 0.1 to 1 mg/rat, i.c.v.) increased urine output and urinary excretion of Na + , K + and Cl 7 and reduced urine osmolality. The diuretic activity was also evident in water-deprived, fasted animals and in fasted, waterloaded rats. 3 NT (0.1 mg/rat, i.c.v.) had no e ect on urine output in fed rats, but reduced the diuretic action of SR 48692 (1 mg/rat, i.c.v.). The opposite result was obtained in fasted, water-loaded animals: NT dosedependently (0.01 and 0.1 mg/rat, i.c.v.) inhibited diuresis and this e ect was signi®cantly inhibited by i.c.v. SR 48692. In this experimental condition, SR 48692 did not further increase the on-going diuresis. 4 The NO synthesis inhibitor N o -nitro-L-arginine methyl ester (L-NAME; 30 mg kg 71 , i.p.) alone had no e ect on urine output in fed rats but prevented the diuretic action of i.c.v. or i.p. SR 48692; Larginine (1 g kg 71 , i.p.) but not D-arginine (1 g kg 71 , i.p.) restored the SR 48692-dependent increase in diuresis. L-NAME had no e ect on furosemide-stimulated diuresis. 5 Systemically administered L-NAME or i.c.v. NT in fasted, water-loaded rats signi®cantly reduced water diuresis but this e ect was no longer seen in animals given i.p. L-arginine. Rats receiving i.c.v. NT, whose diuresis was signi®cantly reduced, also excreted less nitrates and nitrites in urine. 6 Increased diuresis after central or systemic administration of SR 48692 to fed rats was paralleled by increased urinary excretion of nitrates and nitrites, this being consistent with peripheral enhancement of NO production after NT-receptor blockade by SR 48692. The increase in diuresis after furosemide also involved an increase of nitrates and nitrites in urine, but this e ect was about half that attained with an equipotent diuretic dose of SR 48692. 7 In fed rats, the NO donor isosorbide-dinitrate, reduced systolic blood pressure (unlike SR 48692 which did not a ect blood pressure) but also dose-dependently (1 and 5 mg kg 71 , i.p.) stimulated urine output. 8 The overall e ects of SR 48692 strongly support a link between the actions of endogenous NT, AVP and peripheral NO production in the modulation of renal excretion of water, Na + , K + and Cl 7 .

Characterization and localization of leptin receptors in the rat kidney

“…Leptin also lowered significantly (P<0.05) urine osmolality only in the first 2-h period: 757 ±50 mOsm/kg H 2 0 (« = 7) and 479 ±53 mOsm/kg H 2 0 (»= 15) for the control and leptin-treated group, respectively. It is important to note that control parameter values observed in these studies are comparable to those previously described by ourselves and others [24,25].…”

Postnatal Nitric Oxide Inhibition Modifies Neurotensin Effect on ATPase Activity

“…, K ? and Cl - [34]. Present results also favour the view of a link between neurotensin and NO production.…”

Tear film osmolarity in patients with thyroid ophthalmopathy

“…The osmolarity of the tear fi lm samples of the patients with thyroid ophthalmopathy and of the healthy subjects was determined by the freezing point depression technique using an auto-osmometer (OM-6030 AUTO STAT; Daiichi, Kyoto, Japan). 7,8 The osmometer was calibrated by using deionized water and two standard solutions. The recorded data were multiplied by six to obtain the tear fi lm osmolarity values.…”