Role of nitric oxide pathway in hypotensive and renal effects of furosemide during extracellular volume expansion.
OBJECTIVE
In previous studies we demonstrated that the administration of furosemide associated with L-arginine contributes to enhanced hypotension and induces greater water than electrolyte excretion, in both normal and expansion conditions. The aim of the present study was to elucidate the interaction between furosemide and the nitric oxide (NO) system in renal and vascular responses during extracellular volume expansion.


METHODS
Expanded [10% body weight (bw)] and non-expanded anaesthetized male Wistar rats were treated with furosemide (7.5 mg/kg bw). Mean arterial pressure, nitrite and nitrate excretion (NOx) were determined. NADPH-diaphorase activity, a marker of nitric oxide synthase (NOS) activity, was measured histochemically in different segments of the nephron, aorta and renal arteries. NOS activity was determined using an L-[U14C]-arginine substrate in the kidney and aorta of expanded and non-expanded rats, in basal conditions and after furosemide (10 micromol/l).


RESULTS
The hypotensive effect of furosemide was enhanced when NO production was stimulated in expanded and non-expanded animals. The diuretic treatment induced a significant increase in NOx excretion, in NADPH-diaphorase activity in the thick ascending limb of Henle, renal arteries and aorta, and in NOS activity in aorta and kidney in both groups.


CONCLUSIONS
Our results suggest that the hypotensive effect of furosemide may be attributed to NO-mediated vasodilation. The enhanced NOS activity, observed in the renal artery of furosemide-treated rats, could explain the increased renal plasma flow induced by furosemide. In addition, NO-pathway stimulation in the kidney could be one of the mechanisms by which furosemide exerts its diuretic and natriuretic effects, in control and in expansion conditions.
Costa
María A
MA
Cátedra de Fisiología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, IQUIMEFA-CONICET, Capital Federal, Argentina. mcosta@ffyb.uba.ar
Loria
Analía
A
Elesgaray
Rosana
R
Balaszczuk
Ana María
AM
Arranz
Cristina
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001810:Blood Volume / Q000502:physiology; D002250:Carbon Radioisotopes; D002956:Citrulline / Q000493:pharmacokinetics; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology*; D007022:Hypotension / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects
D002250:Carbon Radioisotopes; D004232:Diuretics; D009566:Nitrates; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; D005665:Furosemide; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase