OBJECTIVE: Nitric oxide (NO) blunts the myogenic response (MR) in renal blood flow (RBF) autoregulation. We sought to clarify the contributions to this effect by NO produced through neuronal NO-synthase (nNOS) located in macula densa cells or through endothelial NOS (eNOS) in the afferent arteriolar endothelium. METHODS: RBF autoregulation was studied in anesthetized rats in response to a rapid rise in renal artery pressure (RAP) induced by release of a brief reduction of RAP (20 mmHg for 60 s). According to previous studies the autoregulatory rise in renal vascular resistance within the initial 6 s was interpreted as MR, that between 6 and 25 s as tubuloglomerular feedback (TGF), and that from 25 to 100 s as a third regulatory mechanism. NO-production from nNOS was inhibited using S-methyl-thio-citrulline (SMTC) or N-propyl-l-Arginine (NPA). Global inhibition of all NOS isoforms was achieved using L-NAME (25 mg/kg). RESULTS: Dose-response experiments for SMTC (2-256 mg/kg/min, n=4) revealed RBF-reduction indicating unspecific eNOS-inhibition starting at 16 mg/kg/min (RBF -2±1%). In autoregulation studies SMTC (10 mg/kg/min, n=11) did not significantly reduce RBF (-5±2%), raise RAP (+2±2% from control), or augment MR (67±4 vs. 57±4% of perfect autoregulation, p>0.09). Subsequently given L-NAME elicited the expected strong effects (RBF -37±3%, RAP +22±3% from control, MR 78±4 vs. 57±4% of perfect autoregulation, p<0.05). Similar results were obtained using NPA (30 mg/kg/min into the renal artery, MR 55±4 vs. 59±10%, L-NAME 73±7%, n=3). To mimic the constrictor and pressor effects of L-NAME, Angiotensin II was coinfused with SMTC. Although this manoever lowered RBF (-43±1%) and raised RAP (+18±3%), it did not augment MR (58±3 vs. 54±7%, p>0.4, n=5). CONCLUSIONS: We conclude that the attenuating effect of NO on MR in RBF autoregulation does not depend on NO-production by nNOS in macula densa cells.