Involvement of tumor necrosis factor-alpha in natriuretic response to systemic infusion of nitric oxide synthase inhibitor in anesthetized mice.
Systemic infusion of TNF-alpha exerts renal vasoconstriction but caused marked natriuresis in mice. Similar renal responses were also observed during systemic infusion of nitric oxide (NO) synthase inhibitors as opposed to their usual antinatriuretic responses when administered intrarenally. In the present study, we examined the hypothesis that acute NO blockade systemically induces TNF-alpha generation. which induces this natriuretic response. Renal responses to intravenous infusion of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 0.2 microg x min(-1) x g body wt(-1) for 85 min) and its impact on the plasma level of TNF-alpha were evaluated in anesthetized mice. Plasma TNF-alpha was undetected in untreated mice (n = 7) but was elevated in L-NAME-treated mice (109 +/- 22 pg/ml; P < 0.01 vs. untreated group; n = 7) along with an increase in TNF-alpha protein expression in kidney tissue. L-NAME infusion caused a usual increase in mean arterial pressure (MAP; 98 +/- 3 to 122 +/- 3 mmHg; P < 0.01) and decreases in renal blood flow (RBF; 8.6 +/- 0.3 to 4.4 +/- 0.2 ml x min(-1) x g(-1); P < 0.01) and glomerular filtration rate (GFR; 1.14 +/- 0.07 to 0.77 +/- 0.04 ml x min(-1) x g(-1); P < 0.01) with a marked increase in sodium excretion (U(Na)V; 0.48 +/- 0.10 to 3.52 +/- 0.85 micromol x min(-1) x g(-1); P < 0.01). Interestingly, in mice (n = 7) pretreated with the TNF-alpha blocker etanercept (5 mg/kg sc), the U(Na)V response to l-NAME infusion was markedly blunted (0.58 +/- 0.08 to 1.22 +/- 0.28 micromol x min(-1) x g(-1); P = NS) although responses for MAP, RBF, and GFR were mostly unchanged. However, pretreatment with the superoxide scavenger tempol in mice (n = 7) did not alter the U(Na)V response to L-NAME. These data demonstrate that L-NAME-induced natriuresis is mediated, at least in part, by concomitant generation of TNF-alpha during NO blockade.
Shahid
Mohd
M
Department of Physiology and Tulane Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Francis
Joseph
J
Matrougui
Khalid
K
Majid
Dewan S A
DS
D000768:Anesthesia, General; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D000068800:Etanercept; D016166:Free Radical Scavengers / Q000008:administration & dosage; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007074:Immunoglobulin G / Q000008:administration & dosage; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D009318:Natriuresis / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood*; D015854:Up-Regulation
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000068800:Etanercept; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester
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