Nitric oxide alters renal function and guanosine 3′,5′-cyclic monophosphate

Endothelium-derived relaxing factor (EDRF) activates soluble guanylate cyclase, resulting in an increase in vascular smooth muscle guanosine 3′,5′-cyclic monophosphate (cGMP) levels, which correlates with its relaxing effect. Using a microdialysis technique, we investigated changes in right and left renal interstitial fluid cGMP levels in response to right intrarenal administration of an EDRF inhibitor, N^G-monomethyl-L-arginine (L-NMMA). Studies were conducted in anesthetized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Urine was collected directly from the right and left ureters individually. Changes in the right and left urinary cGMP excretion and renal function in response to cumulative doses of L-NMMA were studied. In the right kidney, 20–100 μg/kg/min L-NMMA caused 1) a dose-dependent decrease in renal interstitial fluid and urinary cGMP levels (p < 0.0001 and p < 0.001, respectively), 2) antinatriuresis (p < 0.01), 3) antidiuresis (p < 0.01), 4) a decrease in renal blood flow (p < 0.01) and glomerular filtration rate (p < 0.01), and 5) a decrease in fractional sodium excretion (p < 0.01). No changes in left renal interstitial fluid and urinary cGMP levels or excretory and hemodynamic function were observed during right intrarenal administration of L-NMMA at 20 and 60 μg/kg/min. L-NMMA at 100 μg/kg/min produced a significant decrease in left renal interstitial fluid (p < 0.01) and urinary (p < 0.01) cGMP levels, antidiuresis (p < 0.01), antinatriuresis (p < 0.01), and decreases in renal blood flow (p < 0.0001), glomerular filtration rate (p < 0.01), and fractional sodium excretion (p < 0.01). These data demonstrate the ability to monitor renal interstitial fluid cGMP levels in anesthetized animals. We conclude that EDRF acts intrarenally to control renal function through the modulation of renal interstitial cGMP.