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Summary:The partIcipation of nitric oxide and vasoactive intestinal peptide (VIP) in the neurogenic regulation of bovine cerebral arteries was investigated, Nitrergic nerve fibers and ganglion-like groups of neurons were revealed by NADPH diaphorase staining in the adventitial layer of bovine cerebral arteries, NADPH diaphorase also was present in endothelial cells but not in the smooth muscle layer. Double immunola beling for neuronal nitric oxide synthase and VIP indicated that both molecules co-localized in the same nerve fibers in these vessels. Transmural nerve stimulation (200 rnA, 0.2 millisec onds, I to 8 Hz) of endothelium-denuded bovine cerebral artery rings precontracted with prostaglandin F2ex, produced tetrodo toxin-sensitive relaxations that were completely suppressed by AP-nitro-L-arginine methyl ester (L-NAME) and by the gua This work was supported by grant 94/0388 from the "Fondo de Investigaciones Sanitarias," Spain, and by PRAXIS XXI (BD/35751 94), Portugal. C Barroso is a recipient of an ENP short-term fellowship from the European Science Foundation. Ms. C. Martin is a recipient of a fellowship from the "Fondo de Investigaciones Sanitarias," Spain.Address correspondence and reprint requests to Dr. Carmen Estrada, Departamento de Fisiologfa, Facultad de Medicina, Universidad Au t6noma de Madrid, Arzobispo Morcillo I, 28029 Madrid, Spain.Abbreviations used: cAMP, cyclic AMP; cGMP, cyclic GMP; EC so , effective concentration 50; Emax, maximum effect; L-NAME, �-nitro L-arginine methyl ester; NANC, nonadrenergic noncholinergic; NO, nitric oxide; NOS, nitric oxide synthase; ODQ, lH-[1,2.4]oxadiazolo [4,3-a]quinoxaline; PBS, phosphate-buffered saline; SQ 22, 536, 9-(tet rahydro-2-furanyl)-9H-purin-6-amine; TNS, transmural nerve stimula tion; VIP, vasoactive intestinal peptide. 977VIP. Transmural nerve stimulation also elicited increases in intracellular cyclic GMP concentration, which were prevented by L-NAME, and small decreases in intracellular cyclic AMP concentration. Addition of VIP to bovine cerebral artery rings without endothelium produced a concentration-dependent re laxation that was partially inhibited by L-NAME, ODQ, and SQ 22,536. The effects of L-NAME and SQ 22,536 were additive. VIP induced a transient increase in intracellular cyclic GMP concentration, which was maximal I minute after VIP addition, when the highest relaxation rate was observed, and which was blocked by L-NAME. It is concluded that nitric oxide produced by perivascular neurons and nerve fibers fully accounts for the experimental neurogenic relaxation of bovine cerebral arteries and that VIP, which also is present in the same perivascular fibers, acts as a neuromodulator by activating neuronal nitric oxide synthase.

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These results demonstrate that nerve supplying cortical vessels in SWD are arranged in a distribution pattern similar to the one observed in human normal cortical veins and suggest that these abnormal vessels are innervated only with noradrenergic sympathetic nerve fibers. This represents a clear difference from the pattern of innervation observed in both normal cortical arteries and veins, and is the consequence of the anatomic and functional dysangiogenic process characteristic of the affected cortical areas in SWD.