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 I (AT(1)). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SAL- and Ang II-infused rats on day 13 after implantation averaged 121 +/-4 (n=28) and 151 +/-5 (n=30), respectively (P<0.05). There were no differences in glomerular filtration rate (GFR) (0.68<plus/minus>0.09 versus 0.59 +/-0.09 mL . min(-1) . g(-1)), renal plasma flow (RPF) (2.66 +/-0.31 versus 2.34 +/-0.39 mL . min(-1) . g(-1)), and absolute sodium excretion (0.37 +/-0.07 versus 0.42 +/-0.09 mu mol . min(-1) . g(-1)). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n=7) or Ang II-infused rats (n=8). 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 (n=9) by 29 +/-4%, 38 +/-4%, and 70 +/-4% compared with control values (P<0.05). The pretreatment by the AT(1) receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n=7) effectively prevented the decrease in RPF (-3<plus/minus>3%) elicited by nNOS inhibition and resulted in an increase in GFR (+25 +/- 12, P<0.05) and a concomitant greater increase in sodium excretion (84<plus/minus>12%, P<0.05) compared with control values. In contrast, in Ang II-infused rats (n= 10) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (-2<plus/minus>2%, -15 +/- 10%, and -14 +/- 10%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II-mediated vasoconstriction in the pre- and 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.
