ROLE OF NITRIC-OXIDE IN EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA ON MICROCIRCULATION IN RAT

The involvement of nitric oxide (NO) in the effects of tumor necrosis factor-alpha (TNF-alpha) on the microcirculation was studied by in vivo microscopy in rat cremaster muscle. We examined second-, third-, and fourth-order arterioles with mean diameters under control conditions of 62.2, 37.4, and 16.9 mu m, respectively. The vasodilation observed after topical administration of 100 ng/ml recombinant TNF-alpha (rTNF-mu) was partly but significantly inhibited when NO synthesis was inhibited by 2 X 10(-4) M N-w-nitro-L-arginine (L-NNA). Almost complete inhibition of the acute vase dilatory effect of rTNF-alpha was found when both NO and prostaglandin synthesis were blocked by simultaneous administration of L-NNA and mefenamic acid. The effect of rTNF-alpha on vasoconstriction in response to norepinephrine (NE) was a dramatic reduction after 2 h of exposure to 1 ng/ml rTNF-alpha. Concomitant administration of 2 X 10(-4) M L-NNA prevented this hyporeactivity for second- and third-order, but not for fourth-order, arterioles. However, at 2 X 10(-3) M, L-NNA totally prevented the hyporeactivity to NE for all arteriolar orders. No changes in vasoconstriction to 70 mM KCl were observed either immediately after rTNF-alpha administration or after 2 h of exposure. We conclude that 1) the direct acute vasodilatory effect of rTNF-alpha on the microcirculation is mediated by both prostaglandins and NO, 2) long exposure to rTNF-alpha diminishes the response of the arterioles to Ne but not to KCl, and 3) this effect is mediated by NO.