Involvement of tumor necrosis factor-α in natriuretic response to systemic infusion of nitric oxide synthase inhibitor in anesthetized mice

Abstract

Systemic infusion of TNF-α 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-α 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 μg·min−1·g body wt−1for 85 min) and its impact on the plasma level of TNF-α were evaluated in anesthetized mice. Plasma TNF-α 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-α 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·min−1·g−1; P < 0.01) and glomerular filtration rate (GFR; 1.14 ± 0.07 to 0.77 ± 0.04 ml·min−1·g−1; P < 0.01) with a marked increase in sodium excretion (UNaV; 0.48 ± 0.10 to 3.52 ± 0.85 μmol·min−1·g−1; P < 0.01). Interestingly, in mice ( n = 7) pretreated with the TNF-α blocker etanercept (5 mg/kg sc), the UNaV response to l-NAME infusion was markedly blunted (0.58 ± 0.08 to 1.22 ± 0.28 μmol·min−1·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 UNaV response to l-NAME. These data demonstrate that l-NAME-induced natriuresis is mediated, at least in part, by concomitant generation of TNF-α during NO blockade.