Role of nNOS in Regulation of Renal Function in Angiotensin II

Previous studies have indicated that in normotensive rats, NO produced by neuronal NO synthase (nNOS) plays an important role in modulating tubuloglomerular feedback (TGF)–mediated afferent arteriolar constriction. It has also been shown that in angiotensin (Ang) II–infused hypertensive rats, there is a reduced ability of nNOS-derived NO to counteract this vasoconstriction. The present study was performed to (1) assess in vivo renal functional responses to intrarenal nNOS inhibition in control and Ang II–infused rats and (2) determine whether changes in renal function following nNOS inhibition are mediated by unopposed stimulation of Ang II receptor subtype 1 (AT1). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SALand Ang II–infused rats on day 13 after implantation averaged 12164 (n528) and 15165 (n530), respectively (P,0.05). There were no differences in glomerular filtration rate (GFR) (0.6860.09 versus 0.5960.09 mL · min · g), renal plasma flow (RPF) (2.6660.31 versus 2.3460.39 mL · min · g), and absolute sodium excretion (0.3760.07 versus 0.4260.09 mmol · min · g). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n57) or Ang II–infused rats (n58). Acute intrarenal administration of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.3 mg/h) decreased GFR, RPF, and sodium excretion in SAL-infused rats (n59) by 2964%, 3864%, and 7064% compared with control values (P,0.05). The pretreatment by the AT1 receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n57) effectively prevented the decrease in RPF (2363%) elicited by nNOS inhibition and resulted in an increase in GFR (125612, P,0.05) and a concomitant greater increase in sodium excretion (84612%, P,0.05) compared with control values. In contrast, in Ang II–infused rats (n510) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (2262%, 215610%, and 214610%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II–mediated vasoconstriction in the preand postglomerular microcirculation. Furthermore, Ang II–infused rats exhibit an impaired ability to release NO by nNOS. Decreased nNOS activity is likely to account at least partially for the enhanced TGF responsiveness in Ang II–infused rats and thus may contribute to the maintenance of hypertension in this model. (Hypertension. 2001;38:280-285.)