TUMOR-NECROSIS-FACTOR-ALPHA INDUCES PIAL ARTERIOLAR DILATION IN NEWBORN PIGS

The present study in piglets was designed to examine cerebrovascular e ffects of tumor necrosis factor-alpha (TNF alpha) and potential mechan isms involved. Anesthetized newborn pigs with closed cranial windows i mplanted were used. Effects of nitric oxide synthase (NOS) inhibitors, N-G-nitro-L-arginine (L-NNA) and aminoguanidine, and a prostaglandin H synthase inhibitor, indomethacin, on pial arteriolar responses to TN F alpha were determined. In addition, cortical cerebrospinal fluid (CS F) prostanoids (PGE(2) and 6-keto-PGF(1 alpha)) and cyclic nucleotides (cAMP and cGMP) were examined as indices of local cerebral production . Diameters of pial arterioles were recorded every 5 min for 30 min fo llowing topical infusion of TNF alpha under the window. CSF was sample d at the end of the 30-min recordings. TNF alpha (10(-8) and 10(-7) M) caused dilation of pial arterioles and increased CSF prostanoids and cyclic nucleotides. Indomethacin blocked TNF alpha-induced vasodilatio n and the increase of prostanoids and cAMP, but not of cGMP. L-NNA and aminoguanidine blocked TNF alpha-induced vasodilation. Both inhibitor s attenuated TNF alpha-induced prostanoid increase. Aminoguanidine blo cked TNF alpha-induced increased cGMP and attenuated the increase in c AMP. These results are consistent with the hypothesis that TNF alpha i ncreases cAMP via prostanoid synthesis. They also suggest that TNF alp ha increases cGMP through nitric oxide synthesis, which, in addition, may promote production of prostanoids and, thus, cAMP.