title: Carboxy-PTIO, a scavenger of nitric oxide, selectively inhibits the increase in medullary perfusion and improves renal function in endotoxemia.
abstract: The acute renal failure associated with septic shock is associated with a high mortality despite dialytic therapies. Endotoxemia leads to marked changes in the distribution of intrarenal perfusion that may be independent of alterations in total renal blood flow or systemic hemodynamics. Modulation of this intrarenal redistribution may protect against acute renal failure. This study examines the effect of carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO), a scavenger of nitric oxide (NO), on systemic and intrarenal hemodynamics measured by laser Doppler flowmetry following the induction of endotoxemia in the anesthetized rat. Infusion of lipopolysaccharide (LPS) led to a prompt reduction in inulin clearance at 60 min, which remained reduced for 6 h in saline-treated rats. Administration of carboxy-PTIO led to a sustained increase in inulin clearance over 360 min post-LPS. During endotoxemia, cortical perfusion fell acutely by 29 +/- 8%, whereas medullary perfusion increased by 71 +/- 11%. The increase in medullary perfusion was potently and selectively inhibited by carboxy-PTIO. We propose that inhibition of medullary hyperemia maintains glomerular hydrostatic pressure, thus leading to the improved renal function during endotoxemia and that scavenging of NO may prove to be a useful therapeutic option in the acute renal failure associated with septic shock.
authors.affiliation: Department of Experimental Medicine and Nephrology, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, United Kingdom.
authors.forename: Colin G M
authors.initials: CG
authors.lastname: Millar
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D019446:Endotoxemia / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology*; D008070:Lipopolysaccharides; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects
chemical_list: D001565:Benzoates; D007093:Imidazoles; D007328:Insulin; D008070:Lipopolysaccharides; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide