Lazaroid and pentoxifylline suppress sepsis-induced increases in renal vascular resistance via altered arachidonic acid metabolism.
Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation. It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid. Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis. Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism. This study demonstrates that sepsis leads to increased renal vascular resistance. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.
Krysztopik
R J
RJ
Department of Surgery and Center for Excellence in Applied Microcirculatory Research, University of Louisville, Louisville, Kentucky 40206, USA.
Matheson
P J
PJ
Spain
D A
DA
Garrison
R N
RN
Wilson
M A
MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D016470:Bacteremia / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000502:physiology; D013929:Thromboxane B2 / Q000096:biosynthesis; D014655:Vascular Resistance / Q000187:drug effects*
D000975:Antioxidants; D010726:Phosphodiesterase Inhibitors; D011281:Pregnatrienes; C074965:U 74389F; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D010431:Pentoxifylline