title: Renal intramedullary infusion of tempol normalizes the blood pressure response to intrarenal blockade of heme oxygenase-1 in angiotensin II-dependent hypertension.
abstract: Previous studies have demonstrated that intramedullary inhibition of heme oxygenase-1 (HO-1) increases the blood pressure and superoxide production response to angiotensin II (Ang II) infusion. The present study was designed to test the hypothesis that increased renal medullary superoxide production contributes to the increase in blood pressure in response to blockade of renal medullary HO-1 in Ang II-induced hypertension. Male C57BL/6J mice (16-24 weeks of age) were implanted with chronic intrarenal medullary interstitial (IRMI) and infused with: saline, tempol (6 mM), the HO-1 inhibitor QC-13 (25 μM), or a combination of tempol + QC-13. Tempol treatment was started 2 days before infusion of QC-13. After 2 days, Ang II was infused subcutaneously at a rate of 1 μg/kg/min for 10 days. Blood pressures on days 7-10 of Ang II infusion alone averaged 150 ± 3 mm Hg in mice receiving IRMI infusion of saline. IRMI infusion of QC-13 increased blood pressure in Ang II-treated mice to 164 ± 2 (P < .05). Renal medullary superoxide production in Ang II-treated mice was significantly increased by infusion of QC-13 alone. Ang II-treated mice receiving IRMI infusion of tempol had a blood pressure of 136 ± 3 mm Hg. Ang II-treated mice receiving IRMI infusion of tempol and QC-13 had a significantly lower blood pressure (142 ± 2 mm Hg, P < .05) than mice receiving QC-13 alone. The increase in renal medullary superoxide production was normalized by infusion of tempol alone or in combination with QC-13. These results demonstrate that renal medullary interstitial blockade of HO-1 exacerbates Ang II-induced hypertension via a mechanism that is dependent on enhanced superoxide generation and highlight the important antioxidant function of HO-1 in the renal medulla.
authors.affiliation: Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA. Electronic address: dstec@umc.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.affiliation: Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
authors.affiliation: Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D007263:Infusions, Parenteral; D007679:Kidney Medulla / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D008565:Membrane Proteins; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C001803:tempol
keywords: Bilirubin; blood pressure; carbon monoxide; superoxide