Endotoxin-induced renal failure. I. A role for altered renal microcirculation.
The pathogenesis of sepsis-induced renal failure is multifactorial and only partially understood. In these studies we evaluated intrarenal microcirculatory changes during endotoxemia and the potential role of nitric oxide (NO) and endothelin in these changes. In anesthetized rats endotoxin infusion [lipopolysaccharide (LPS), Escherichia coli serotype 0127:B8; 10 mg/kg/h] resulted in hypotension and a transient enhancement of renal blood flow, with cortical vasodilation and a loss of outer medullary vasodilatory response to hypotension. The initial cortical vasodilation was abolished by the NO synthase inhibitor NG-nitro-L-arginine methyl ester, but not by indomethacin. Direct NO measurements disclosed a gradual rise in cortical NO, despite the waning vasodilatory effect, suggesting antagonizing vasoconstrictive stimuli. In rats pretreated by LPS (1 mg/kg i.p. 1 day earlier) the renal blood flow was reduced to 55% of that of controls. Moreover, the vasodilatory response to LPS infusion was converted into profound cortical and medullary vasoconstriction. In these preconditioned rats the endothelin receptor antagonist bosentan evoked a vasodilatory response and attenuated the vasoconstrictive reaction to LPS infusion. The infusion of another LPS (E. coli serotype 0111:B4) exerted predominant and protracted renal vasodilation without hypotension. In conclusion, different LPS exert diverse systemic and renal hemodynamic responses. The 0127:B8 serotype attenuates renal medullary vasodilation during hypotension, exerts transient cortical vasodilation, and following repeated exposure induces profound renal vasoconstriction. NO and endothelin participate in LPS-induced vascular responses that may predispose to hypoxic tubular damage.
Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel. Heyman@cc.huji.ac.il
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Heyman
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Darmon
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Goldfarb
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Bitz
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Shina
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Rosen
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Brezis
D000818:Animals; D001783:Blood Flow Velocity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016232:Endothelins / Q000502:physiology; D019446:Endotoxemia / Q000150:complications; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000209:etiology* / Q000503:physiopathology; D014664:Vasodilation
D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D004731:Endotoxins; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin