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

1.我们研究了内毒素是否参与了L-精氨酸对去内皮大鼠胸主动脉的舒缩作用，这种作用可能是通过血管平滑肌一氧化氮合酶来实现的。在无内毒素的情况下，L-精氨酸对动脉几乎没有任何松弛作用。用内毒素处理动脉时，10 mU的L-精氨酸引起血管松弛，延迟期为2-4小时，反复应用L-精氨酸后，松弛程度增加，在数小时内达到稳定水平。内毒素浓度的升高缩短了迟滞期，增强了松弛程度，降低了松弛动脉所需的L-精氨酸的阈值浓度。在内毒素刺激的动脉中，L-精氨酸在诱导松弛所必需的浓度下刺激循环GMP的产生。预防性应用抑制一氧化氮合酶诱导的放线菌素D或地塞米松预防内毒素诱导的L…更多的精氨酸诱导的松弛和环状GMP的形成。抑制内毒素作用的多粘菌素B也能阻止L-精氨酸诱导的内毒素敏感性松弛和环化GMP的形成。去离子水配制克雷布斯溶液时，贮液器内的内毒素水平高于L-精氨酸诱导的松弛和循环GMP合成所需的水平。这些结果提示，内毒素通过在血管平滑肌中表达一氧化氮合酶，触发了L精氨酸诱导的时间依赖性松弛。我们观察了酪氨酸激酶抑制剂对内毒素诱导的L-精氨酸诱导的大鼠胸主动脉松弛的影响。预防性应用酪氨酸激酶抑制剂赫比霉素A、金雀异黄素和erbstatin类似物选择性地阻止了脂多糖诱导的L-精氨酸诱导的松弛和环状GMP的形成。这些结果表明，酪氨酸激酶可能通过脂多糖触发的信号通路中蛋白酪氨酸的磷酸化，触发可诱导的NO合成酶的表达，从而介导L-精氨酸诱导的动脉松弛。较少

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