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 microns, respectively. The vasodilation observed after topical administration of 100 ng/ml recombinant TNF-alpha (rTNF-alpha) was partly but significantly inhibited when NO synthesis was inhibited by 2 x 10(-4) M N omega-nitro-L-arginine (L-NNA). Almost complete inhibition of the acute vasodilatory effect of rTNF-alpha was found when both NO and prostaglandin synthesis were blocked by simultaneous administration of L-NNA and mefanamic 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.
Baudry
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N
Laboratoire d'Etude de la Microcirculation, Hôpital F. Widal, Paris, France.
Vicaut
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E
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009132:Muscles / Q000098:blood supply; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019335:Nitroarginine; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D008070:Lipopolysaccharides; D011453:Prostaglandins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D009569:Nitric Oxide; D011189:Potassium Chloride; D001120:Arginine; D009638:Norepinephrine