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Tumor necrosis factor alpha (TNF alpha) increases nitric oxide (NO) synthase in vascular endothelium, but it inhibits endothelium-dependent relaxation (EDR) of vascular smooth muscle. We tested whether TNF alpha 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 (donor)-relaxed endothelium-rubbed bovine coronary artery (BCA) (detector). Moreover, effluent from the donor stimulated with acetylcholine (ACh) or bradykinin (BK) (0.001 to 100 nmol) relaxed the detector. Direct application of these agonists to the detector failed to produce relaxation. Basal and agonist-stimulated effluent from the donor treated with L-NG-monomethylarginine (LNMMA) (100 microM) suppressed effluent-mediated relaxation of the detector. ACh and BK released LNMMA-inhibitable nitrite and nitrate from the BPA. Thus, the effluent contained NO. Exposure of the donor to TNF alpha (1.25 micrograms/ml) for 60 min did not affect basal release of NO, but it attenuated bioassayable and chemiluminescence-detectable NO release by ACh and BK. The inhibition of NO release was directly related to the magnitude of inhibition of EDR by ACh and BK. Thus, TNF alpha 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 physiologic mechanism of regulation of NO in the endothelium.
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