8335573

pubmed:Citation

5

Tumor necrosis factor-alpha (TNF-alpha) stimulates nitric oxide (NO) in vascular endothelium by induction of the enzyme NO synthase II (NOS II). We examined the effects of TNF-alpha on 1) endothelium-dependent (EDR) and endothelium-independent (EIR) relaxation and 2) contraction of bovine intralobar pulmonary arteries (BPA) and veins (BPV) in vitro. Acetylcholine (ACh), bradykinin (BK), histamine, and A23187 produced EDR of BPA contracted with a 50% effective concentration of U-46619 (15 nM), because relaxation was abolished by endothelium-rubbing and attenuated by L-NG-mono-methylarginine (L-NMMA; 300 microM). TNF-alpha (0.00417, 0.0417, 0.417, and 1.25 micrograms/ml) incubated with BPA for 60 min inhibited EDR of the BPA to ACh, BK, and histamine. The effects of TNF required 30 min for onset. Recovery of EDR occurred 3-4 h after washout of TNF-alpha. Pentoxifylline (1 microM) did not affect ACh-induced EDR but selectively reversed TNF-alpha-mediated inhibition of ACh-induced EDR. TNF-alpha-mediated inhibition of EDR was not reversible by L-NMMA, an inhibitor of NOS I and NOS II, the cyclooxygenase inhibitor ibuprofen, or CV-3908 (1 microM), a platelet-activating factor antagonist. The inhibitory effect of TNF-alpha on EDR was not mediated by nonspecific sensitization of the endothelium to human protein because recombinant human granulocyte colony-stimulating factor (10, 50, and 500 x 10(3) U/ml) did not affect EDR of BPA. The effect of TNF-alpha was specific for release of NO from the endothelium of BPA because TNF-alpha did not affect 1) EDR of BPV to ACh, BK, or ATP; 2) EIR of BPA or BPV to nitroprusside; and 3) contraction of either BPA or BPV to KCl, U-46619, histamine, norepinephrine, or serotonin. Thus TNF-alpha appears to selectively inhibit receptor-mediated EDR and NO release in BPA. TNF-alpha-mediated inhibition of EDR differs from that of L-arginine-based inhibitors and may represent an endogenous physiological mechanism of regulation of NO in the endothelium.

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IM

MEDLINE

8750-7587

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NLM

2394-403

pubmed-meshheading:8335573-15-Hydroxy-11 alpha,9..., pubmed-meshheading:8335573-Acetylcholine, pubmed-meshheading:8335573-Animals, pubmed-meshheading:8335573-Arginine, pubmed-meshheading:8335573-Cattle, pubmed-meshheading:8335573-Endothelium, Vascular, pubmed-meshheading:8335573-Histamine, pubmed-meshheading:8335573-Ibuprofen, pubmed-meshheading:8335573-Muscle, Smooth, Vascular, pubmed-meshheading:8335573-Muscle Contraction, pubmed-meshheading:8335573-Muscle Relaxation, pubmed-meshheading:8335573-Norepinephrine, pubmed-meshheading:8335573-Pentoxifylline, pubmed-meshheading:8335573-Potassium Chloride, pubmed-meshheading:8335573-Prostaglandin Endoperoxides, Synthetic, pubmed-meshheading:8335573-Pulmonary Artery, pubmed-meshheading:8335573-Pulmonary Veins, pubmed-meshheading:8335573-Tumor Necrosis Factor-alpha, pubmed-meshheading:8335573-Vasoconstrictor Agents, pubmed-meshheading:8335573-omega-N-Methylarginine

Tumor necrosis factor-alpha inhibits endothelium-dependent relaxation.

Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't