TUMOR-NECROSIS-FACTOR INHIBITS STIMULATED BUT NOT BASAL RELEASE OF NITRIC-OXIDE

Tumor necrosis factor alpha (TNFalpha) increases nitric oxide (NO) syn thase in vascular endothelium, but it inhibits endothelium-dependent r elaxation (EDR) of vascular smooth muscle. We tested whether TNFalpha inhibits the response to, or release of, NO in bovine pulmonary artery (BPA) using the technique of perfusion-superfusion bioassay and ozone chemiluminescence. Effluent from the perfused BPA with endothelium (d onor)-relaxed endothelium-rubbed bovine coronary artery (BCA) (detecto r). Moreover, effluent from the donor stimulated with acetylcholine (A Ch) or bradykinin (BK) (0.001 to 100 nmol) relaxed the detector. Direc t application of these agonists to the detector failed to produce rela xation. Basal and agonist-stimulated effluent from the donor treated w ith L-N(G)-monomethylarginine (LNMMA) (100 muM) suppressed effluent-me diated relaxation of the detector. ACh and BK released LNMMA-inhibitab le nitrite and nitrate from the BPA. Thus, the effluent contained NO. Exposure of the donor to TNFalpha (1.25 mug/ml) for 60 min did not aff ect basal release of NO, but it attenuated bioassayable and chemilumin escence-detectable NO release by ACh and BK. The inhibition of NO rele ase was directly related to the magnitude of inhibition of EDR by ACh and BK. Thus, TNFalpha selectively inhibits receptor-mediated release of NO without affecting basal release of NO. This effect differs from that of L-arginine-based inhibitors of NO and represents a unique phys iologic mechanism of regulation of NO in the endothelium.