Myoglobin depletes renal adenine nucleotide pools in the presence and absence of shock.
To assess whether myoglobin adversely affects renal adenylate pools, rats were infused with purified myoglobin (50 mg/100 g body wt) for two hours and renal ATP, ADP, and AMP levels were measured in the absence of shock, after 25 minutes of hemorrhagic shock (55 to 60 mm Hg) or 30 minutes post-recovery. In the absence of shock, myoglobin lowered ATP by 24% (assessed 65 min post-infusion) without affecting renal blood flow (RBF). This effect was completely blocked by deferoxamine (DFO) treatment and it could not be reproduced by ribonuclease infusion (a non-Fe containing, but filtered, protein). Myoglobin + shock caused a three- to fourfold greater decline in ATP than did shock alone despite comparable RBFs. Shock plus myoglobin, but neither one alone, induced substantial S1/S2 proximal tubular morphologic damage and a severe reduction in creatinine clearance, confirming synergistic injury. Ribonuclease completely reproduced myoglobin's effect on shock-induced adenylate profiles. DFO +/- hydroxyl radical scavenger therapy (Na benzoate) did not block the myoglobin shock effect on adenylate pools. Post-shock adenylate recovery was not compromised by myoglobin pre-treatment. If renal artery occlusion (RAO), rather than shock, was used as the ischemic challenge, myoglobin had no discernible impact on adenine nucleotide content. This study concludes that: 1) myoglobin modestly lowers baseline adenylate pools due to an Fe dependent mechanism; 2) myoglobin drastically accentuates shock-induced adenylate depletion by a non-hemodynamic/non-Fe dependent mechanism; 3) myoglobin nephrotoxicity cannot be attributed solely to tissue iron loading; and 4) the RAO model can completely mask important influences on ischemic cellular energetics.(ABSTRACT TRUNCATED AT 250 WORDS)
Zager
R A
RA
Department of Medicine, University of Washington, Seattle.
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000627:therapeutic use; D019817:Benzoic Acid; D003676:Deferoxamine / Q000627:therapeutic use; D005260:Female; D006420:Hemeproteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D009211:Myoglobin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012078:Renal Artery Obstruction / Q000150:complications; D012260:Ribonucleases / Q000494:pharmacology; D012771:Shock, Hemorrhagic / Q000378:metabolism*
D000227:Adenine Nucleotides; D001565:Benzoates; D006420:Hemeproteins; D009211:Myoglobin; D019817:Benzoic Acid; D012260:Ribonucleases; D003676:Deferoxamine