NEGATIVE MODULATION OF NITRIC-OXIDE PRODUCTION BY NEUROTENSIN AS A PUTATIVE MECHANISM OF THE DIURETIC ACTION OF SR-48692 IN RATS

1 We investigated the effect of the non-peptide neurotensin (NT) antag onist 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(-1), p.o. 0.03 to 1 mgkg (-1), i.p. and 0.1 to 1 mu g/rat, i.c.v.) increased urine output and u rinary excretion of Na+, K+ and Cl- and reduced urine osmolality. The diuretic activity was also evident in water-deprived. fasted animals a nd in fasted, water-loaded rats. 3 NT (0.1 mu g/rat, i.c.v.) had no ef fect on urine output in fed rats, but reduced the diuretic action of S R 48692 (1 mu g/rat, i.c.v.). The opposite result a as obtained in fas ted, water-loaded animals: NT dose-dependently (0.01 and 0.1 mu g/rat, i.c.v.) inhibited diuresis and this effect was significantly inhibite d by i.c.v. SR 48692. In this experimental condition, SR 48692 did not further increase the on-going diuresis. 5 Systemically administered L -NAME or i.c.v. NT in fasted, water-loaded rats significantly reduced water diuresis brit this effect was no longer seen in animals given i. p. L-arginine. Rats receiving i.c.v. NT, whose diuresis was significan tly reduced, also excreted less nitrates and nitrites in urine. 6 Incr eased diuresis after central or systemic administration of SR 48692 to fed rats was paralleled by increased urinary excretion of nitrates an d nitrites, this being consistent with peripheral enhancement of NO pr oduction after NT-receptor blockade by SR 48692. The increase in diure sis after furosemide also involved an increase of nitrates and nitrile s in urine. but this effect was about half that attained with an equip otent diuretic dose of SR 48692. 7 In fed rats, the NO donor isosorbid e-dinitrate, reduced systolic blood pressure (unlike SR 48692 which di d not affect blood pressure) but also dose-dependently (1 and 5 mgkg(- 1), i.p.) stimulated urine output. 8 The overall effects of SR 48692 s trongly support a link between the actions of endogenous NTI AVP and p eripheral NO production in the modulation of renal excretion of water, Na+, K+ and Cl-.