Takizawa S, Ozaki H, Karaki H
Department of Veterinary Pharmacology, Graduated School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Japan.
Eur J Pharmacol. 1997 Jul 9;330(2-3):143-50. doi: 10.1016/s0014-2999(97)00164-7.
Stimulation of vascular smooth muscle by bacterial lipopolysaccharide has been shown to produce interleukin-1beta and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1beta-induced relaxation, we examined the effects of interleukin-1beta on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1beta (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine (1 microM) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, N(G)-monomethyl-L-arginine (L-NMMA, 100 microM), prevented the inhibitory effect of interleukin-1beta. After treatment with interleukin-1beta for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither L-NMMA (100 microM) nor aminoguanidine (100 microM) reversed the inhibition, whereas methylene blue (10 microM) partially reversed the inhibition. After treatment with interleukin-1beta for 12 or 24 h, the cyclic GMP content increased but to a level lower than that obtained with a 6-h treatment. The effects of sodium nitroprusside (1 microM) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1beta treatment. In contrast, the 24-h interleukin-1beta treatment did not change the ability of 8-bromo-cGMP to relax the phenylephrine-stimulated aorta. Addition of L-NMMA (1 mM) during the 24 h treatment prevented NO production and preserved the sodium nitroprusside-induced cGMP generation by interleukin-1beta. The 24 h interleukin-1beta treatment increased the threshold concentration of KCl needed to induce contraction without changing the maximum contraction. In the presence of 25.4 mM KCl or the non-selective K+ channel inhibitor, tetraethylammonium, the inhibitory effect of the 24-h interleukin-1beta treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1beta inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1beta, the NO/cyclic GMP system is activated. After a 24-h interleukin-1beta treatment, in contrast, the NO/cyclic GMP system may be desensitized and the contraction of vascular smooth muscle is inhibited by another mechanism, possibly membrane hyperpolarization.
细菌脂多糖对血管平滑肌的刺激已被证明可产生白细胞介素 - 1β并在感染性休克中诱导血管舒张。为了解白细胞介素 - 1β诱导舒张的机制，我们研究了白细胞介素 - 1β对血管平滑肌收缩性和环鸟苷酸含量的影响。用白细胞介素 - 1β（20 ng/ml）处理大鼠主动脉6小时后，环鸟苷酸含量增加，去氧肾上腺素（1 microM）诱导的收缩受到部分抑制。一氧化氮（NO）合酶抑制剂N(G)-单甲基 - L - 精氨酸（L - NMMA，100 microM）可阻止白细胞介素 - 1β的抑制作用。用白细胞介素 - 1β处理24小时后，去氧肾上腺素诱导的收缩受到更强抑制。L - NMMA（100 microM）和氨基胍（100 microM）均不能逆转这种抑制作用，而亚甲蓝（10 microM）可部分逆转这种抑制作用。用白细胞介素 - 1β处理12或24小时后，环鸟苷酸含量增加，但低于6小时处理所达到的水平。硝普钠（1 microM）抑制去氧肾上腺素诱导的收缩并增加环鸟苷酸含量的作用在24小时白细胞介素 - 1β处理后明显受到抑制。相反，24小时白细胞介素 - 1β处理并未改变8 - 溴 - 环鸟苷酸舒张去氧肾上腺素刺激的主动脉的能力。在24小时处理期间添加L - NMMA（1 mM）可阻止NO生成并保留白细胞介素 - 1β诱导的硝普钠介导的环鸟苷酸生成。24小时白细胞介素 - 1β处理增加了诱导收缩所需的氯化钾阈值浓度，而不改变最大收缩力。在存在25.4 mM氯化钾或非选择性钾通道抑制剂四乙铵的情况下，24小时白细胞介素 - 1β处理对去氧肾上腺素诱导的收缩的抑制作用得以恢复。这些结果表明，白细胞介素 - 1β通过一种时间依赖性的双重机制抑制血管平滑肌收缩。用白细胞介素 - 1β处理6小时后，NO/环鸟苷酸系统被激活。相反，用白细胞介素 - 1β处理24小时后，NO/环鸟苷酸系统可能脱敏，血管平滑肌的收缩通过另一种机制被抑制，可能是膜超极化。
