Increasing oxidative stress with molsidomine increases blood pressure in genetically hypertensive rats but not normotensive controls.
Spontaneously hypertensive rats (SHR) have a higher level of oxidative stress and exhibit a greater depressor response to a superoxide scavenger, tempol, than normotensive Wistar-Kyoto rats (WKY). This study determined whether an increase in oxidative stress with a superoxide/NO donor, molsidomine, would amplify the blood pressure in SHR. Male SHR and WKY were given molsidomine (30 mg.kg(-1).day(-1)) or vehicle (0.01% ethanol) for 1 wk, and blood pressure, renal hemodynamics, nitrate and nitrite excretion (NOx), renal superoxide production, and expression of renal antioxidant enzymes, Mn- and Cu,Zn-SOD, catalase, and glutathione peroxidase (GPx), were measured. Renal superoxide and NOx were higher in control SHR than in WKY. Molsidomine increased superoxide by approximately 35% and NOx by 250% in both SHR and WKY. Mean arterial blood pressure (MAP) was also higher in control SHR than WKY. Molsidomine increased MAP by 14% and caused renal vasoconstriction in SHR but reduced MAP by 16%, with no effect on renal hemodynamics, in WKY. Renal expression of Mn- and Cu,Zn-SOD was not different between SHR and WKY, but expression of catalase and GPx were approximately 30% lower in kidney of SHR than WKY. The levels of Mn- and Cu,Zn-SOD were not increased with molsidomine in either WKY or SHR. Renal catalase and GPx expression was increased by 300-400% with molsidomine in WKY, but there was no effect in SHR. Increasing oxidative stress elevated blood pressure further in SHR but not WKY. WKY are likely protected because of higher bioavailable levels of NO and the ability to upregulate catalase and GPx.
Fortepiani
Lourdes A
LA
Dept. of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
Reckelhoff
Jane F
JF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008981:Molsidomine / Q000494:pharmacology*; D009566:Nitrates / Q000652:urine; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000652:urine; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D011506:Proteins; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D008981:Molsidomine; D010088:Oxidoreductases