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

Abstract

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-hydroxy-1 -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.)Key Words l mtnc oxide l vasculature l enzymes R ecent studies have mdlcated that the effects of many renal vasodllators are dependent on the release of NO from the endothehum Blockade of NO synthesis increases arterial pressure, decreases RBF, and potentiates tubuloglomerular feedback responses. 1 These results indicate that tonic release of NO plays an important modulatory role m the regulation of both renal and penpheral vascular tone. It 1s generally assumed that the vasodllatory effects of NO are mediated by cGMP secondary to shmulatlon of guanylyl cyclase 2.3 This concluslon 1s based on the observations that endothehum-dependent vasodilators and NO donors increase cGMP m vascular tissue and that methylene blue and other mhlbltors of guanylyl cyclase m many vessels can elm-nnate the vasodilatory response However, this generalized scheme for NO-induced vasodllatlon has been questioned ...

Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension

“…24 To exclude that the actions of AUDA were a consequence of an unspecific inhibition of the -hydroxylase, the effect of AUDA on vascular tone was compared with that of DDMS, an inhibitor of the -hydroxylase. 25 Only the latter compound affected the tension of the isolated carotid artery from angiotensin II-treated mice, which underscores the specificity of AUDA but also demonstrates that the sEH has no role in the direct control of carotid artery tone in mice.…”

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

“…To evaluate the role of CYP450 4A enzymes in regulating arteriolar tone, we used two different inhibitors: 17-octadecynoic acid (17-ODYA, Sigma Chemical, St. Louis, MO), a suicide substrate inhibitor of CYP450 4A -hydroxylases (19,51) that can also block CYP450 epoxygenase activity (51), and the more specific inhibitor of CYP450 4A -hydroxylase, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) (2). In the first set of experiments, 17-ODYA (1 ϫ 10 Ϫ5 M) was topically applied to the muscle for 30 min while superfusion was stopped.…”

Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation

“…Reactive nitrogen species can modulate the activity of lipidoxidizing enzymes such as cytochrome P450 4A, 44 12-and 15-LOX, and prostaglandin (PG) endoperoxide synthase (PGHS, or cyclooxygenase). These enzymes metabolize unsaturated fatty acids to bioreactive products, such as prostaglandins, leukotrienes, and thromboxanes.…”