Inhibition of 20-HETE Production Contributes to the Vascular Responses to Nitric

N~tnc oxide (NO) Inhibits a variety of heme-contammg enzymes, mcludmg NO synthase and cytochrome P4501Al and 2Bl The present study exammed whether NO mhlblts the production of 20-hydroxyelcosatetraenolc acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO Sodium mtroprusslde (SNP, lo-‘, lo-“, and 10m3 mol/L) reduced the productlon of 20-HETE by renal mlcrosomes incubated with arachldomc acid to 71+5%, 29t4%, and 4+2% of control, respectlvely (n=S) Slmllar results were obtained with the use of 1-propanamme, 3-(2-hydroxy-2-mtroso-1-propylhydrazmo) (n=3) To determme whether mhlbitlon of 20-HETE contributes to the vasodllatory effects of NO, the effects of dlbromo-dodecenylmethylsulfinude (DDMS), a selective mhlbltor of the formatlon of 20-HETE, on the response to SNP (lo-’ to 10m3 mol/L) were examined m rat renal artenoles preconstructed with phenylephrme (n=.5) SNP increased vascular diameter m a concentrafion-dependent manner to 82t4% of control After DDMS (25 ymol/L), SNP (lo-’ mol/L) increased vascular diameter by only 17+3% The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to mfuslon of an NO donor and a synthase mhibltor were also examined m thlobutabarbltal-anesthetrzed, Sprague-Dawley rats Infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/mm reduced MAP by 16+2, 3023,40t5, and 48?5 mm Hg and lowered renal vascular resistance (RVR) by 15+3%, 26?2%, 30?3%, and 34?4% of control After DDMS (10 mg/kg, n=7 rats), the MAP and RVR responses to I-hexamme, 6-(2-hydroxy1 -methyl-2-mtrohydrazmo)N-methyl (MAHMA NONOate) averaged only 20% of those seen durmg control In other expenments, MAP Increased by 3224% and RBF fell to 56+5% of control after admmlstratlon of N-mtro-L-argmme (L-NArg) (10 mg/kg IV) After DDMS (10 mg/kg, n=7 rats), MAP Increased by only 19+4% and RBF fell by only 724% after L-NArg These results indicate that NO mhlblts cytochrome P4504A enzymes and that mhlbltlon of the production of 20-HETE contributes to the vasodllatory effects of NO (Hypertension. 1997;29[part 2]:320-325.)