Studes on the L-arginine-derived, endothelium-independent relaxing factor

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1. We examined whether endotoxin contributes to L-arginine-induced relaxation of endothelium-denuded rat thoracic aorta, which apears to be mediated by nitric oxide synthase in the vascular smooth muscle.2. In the absence of endotoxin, L-arginine induced scarcely any relaxation of the arteries. Treatment of the arteries with endotoxin initiated ralaxation in response to 10 muM L-arginine with lag periods of 2-4 hr, and degree of relaxation increased on repeated application of L-arginine to reach a consistent level in several hours. Increase in the concentration of endotoxin shortened the lag period, enhanced the degree of relaxation and lowered the threshold concentration of L-arginine required to relax the arteries. In endotoxin-primed arteries, L-arginine at concentrations necessary to induce relaxation stimulated cyclic GMP production.3. Prophylactic appliction of actinomycin D or dexamethasone, which inhibits induction of nitric oxide synthase, prevented induction by endotoxin of L … More -arginine-induced relaxation and cyclic GMP formation. Polymyxin B, which inhibits the action of endotoxin, also prevented development of endotoxin-sensitized relaxation and cyclic GMP formation inducded by L-arginine.4. When the Krebs solution was prepared using de-ionized water, the amount of endotoxin in the reservoir was above the level required to initiate L-arginine-induced relaxation and cyclic GMP fotmation.5. These results suggest that endotoxin triggered time-dependent development of L-arginine-induced relaxation by expressing nitric oxide synthase in the vascular smooth muscle.6. We examined the effects of tyrosine kinase inhibitors on the endotoxin(LPS)-primed, L-arginine-induced relaxation of rat thoracic aorta.7. Prophylactic application of the tyrosine kinase inhibitors herbimycin A, genistein and erbstatin analog selectively prevented the initiation by LPS of L-arginine-induced relaxation and cyclic GMP formation.8. These results suggest that tyrosine kinase mediates the L-arginine-induced relaxation of the arteries, probably through protein tyrosine phosphorylation in the LPS-triggered signaling pathway that triggers expression of an inducible NO synthase producing NO. Less