Contributions of 20-HETE to the antihypertensive effects of Tempol in Dahl salt-sensitive rats.
The present study evaluated whether reactive oxygen species-induced alterations in bioavailability of 20-HETE in the kidney contribute to the antihypertensive and renoprotective actions of antioxidant therapy with Tempol in the Dahl salt-sensitive (DS) rat. Superoxide inhibited the synthesis of 20-HETE by renal cortical microsomes and enhanced breakdown of 20-HETE to a more polar product. Addition of Tempol (1 mmol/L) to the drinking water reduced mean arterial pressure from 187+/-9 to 160+/-3 mm Hg in DS rats fed an 8%-NaCl diet for 2 weeks. 20-HETE excretion rose from 117+/-11 to 430+/-45 ng/day, and 8-isoprostane excretion fell from 14+/-1 to 8+/-1 ng/day. Tempol also increased creatinine clearance and reduced the severity of renal damage in DS rats fed a high-salt diet. Blockade of NO synthase with NG-nitro-L-arginine methyl ester (25 mg/kg per day) did not attenuate the antihypertensive or renoprotective actions of Tempol in DS rats. However, chronic blockade of the formation of 20-HETE with N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) blunted the antihypertensive and renoprotective effects of Tempol. These findings indicate that the antihypertensive and renoprotective effects of reducing oxidative stress with Tempol depends in part on increasing the bioavailability of 20-HETE in the kidney.
Hoagland
Kimberly M
KM
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Maier
Kristopher G
KG
Roman
Richard J
RJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives*; D028441:F2-Isoprostanes / Q000652:urine; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000502:physiology* / Q000652:urine; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D013113:Spin Labels; D013481:Superoxides / Q000494:pharmacology
D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D028441:F2-Isoprostanes; D006893:Hydroxyeicosatetraenoic Acids; D013113:Spin Labels; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D015237:Dinoprost; C001803:tempol