Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat. I. Role of reactive oxygen species.
2,3-Dimercaptosuccinic acid (DMSA), a sulfhydryl-containing chelator, has previously been shown to reduce mean blood pressure in lead-treated rats. In the present study we have demonstrated that DMSA (0.5% for 5 days every 2 weeks) also reduces mean blood pressure in the Dahl salt-sensitive (SS) rat. Six-week-old Dahl SS and salt resistant (SR) rats were placed on a 0.3% NaCl diet for two weeks, followed by an 8% NaCl diet for four weeks. Eight SS and 8 SR rats remained untreated while 8 SS and 8 SR rats were treated with DMSA. DMSA treatment ameliorated the mean blood pressure rise in the Dahl SS rats (141 +/- 5 vs. 120 +/- 4 mm Hg at 6 weeks, P < 0.001). Nephrosclerosis was severe in untreated SS rats but absent in treated SS rats as well as in both treated and untreated SR rats. Reactive oxygen species formation, as assessed by kidney cortex content of malondialdehyde (MDA) and immunohistochemical demonstration of nitrotyrosine (a byproduct of peroxynitrite) in interlobular arteries, was increased in Dahl SS rats, but abolished by DMSA (MDA 9.65 +/- 0.33 nmol/g wet wt, untreated SS, vs. 6.46 +/- 0.51, treated SS, P < 0.001). The anti-nephrosclerotic action of DMSA was clearly disproportionate to the reduction in blood pressure. We conclude that the effect of DMSA was related instead to the reactive oxygen species scavenging properties of the thiol groups.
Gonick
H C
HC
Department of Medicine, UCLA School of Medicine, USA.
Cohen
A H
AH
Ren
Q
Q
Saldanha
L F
LF
Khalil-Manesh
F
F
Anzalone
J
J
Sun
Y Y
YY
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002614:Chelating Agents / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D007150:Immunohistochemistry; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009400:Nephrosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012077:Renal Artery / Q000473:pathology; D012982:Sodium, Dietary / Q000494:pharmacology; D004113:Succimer / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000959:Antihypertensive Agents; D002614:Chelating Agents; D016877:Oxidants; D017382:Reactive Oxygen Species; D012982:Sodium, Dietary; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D004113:Succimer