Wu C C, Chen S J, Yen M H
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Am J Physiol. 1998 Oct;275(4):H1148-57. doi: 10.1152/ajpheart.1998.275.4.H1148.
We investigated whether a complete inhibition of nitric oxide (NO) formation caused by bacterial endotoxin (lipopolysaccharide, LPS) in vivo prevents the hypotension and restores the vascular hyporeactivity to normal in vivo and ex vivo. The combination of dexamethasone (Dex; 3 mg/kg at 30 min before LPS) plus aminoguanidine (AG; 15 mg/kg at 2 h after LPS) inhibited the overproduction of nitrate (an indicator of NO) in the plasma and aortic smooth muscle and also prevented the development of the delayed hypotension in rats treated with LPS for 6 h. However, the vascular hyporeactivity to norepinephrine (NE) was only partially improved either in vivo or ex vivo in endotoxemic rats treated with Dex plus AG. Pretreatment of aortic rings with Nomega-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2, 4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced the contraction to NE in rings obtained from LPS-treated rats, but not in those from Dex plus AG-treated endotoxemic rats. Methylene blue, an inhibitor of soluble guanylyl cyclase (GC), completely restored contractions to NE and aortic cGMP levels to normal either in LPS-treated rats or in Dex plus AG-treated endotoxemic rats, whereas the cGMP level was partially inhibited by ODQ in LPS-treated rats only. These results suggest that non-NO mediator(s) also activates soluble GC during endotoxemia. Interestingly, we found that in the presence of tetraethylammonium (an inhibitor of K+ channels) plus L-NAME or charybdotoxin [a specific inhibitor of large-conductance Ca2+-activated K+ (KCa) channels] plus ODQ, the vascular hyporeactivity to NE in the LPS-treated group was also completely restored to normal. In addition, in the presence of L-NAME or ODQ, the vascular hyporeactivity to high K+ was abolished in rings from the LPS-treated group. These results suggest that LPS causes the production of other mediator(s), in addition to NO, which also stimulates soluble GC (i.e., increases the formation of cGMP) and then activates the large-conductance KCa channels in the vascular smooth muscle causing vascular hyporeactivity.
我们研究了体内细菌内毒素（脂多糖，LPS）引起的一氧化氮（NO）生成完全抑制是否能预防低血压，并使体内和体外血管低反应性恢复正常。地塞米松（Dex；LPS注射前30分钟给予3mg/kg）加氨基胍（AG；LPS注射后2小时给予15mg/kg）的联合用药抑制了血浆和主动脉平滑肌中硝酸盐（NO的指标）的过量生成，并且还预防了LPS处理6小时的大鼠出现延迟性低血压。然而，在用Dex加AG处理的内毒素血症大鼠中，体内或体外对去甲肾上腺素（NE）的血管低反应性仅得到部分改善。用Nω-硝基-L-精氨酸甲酯（L-NAME）或1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）预处理主动脉环可增强LPS处理大鼠的主动脉环对NE的收缩反应，但对Dex加AG处理的内毒素血症大鼠的主动脉环则无此作用。亚甲蓝，一种可溶性鸟苷酸环化酶（GC）的抑制剂，可使LPS处理大鼠或Dex加AG处理的内毒素血症大鼠对NE的收缩反应和主动脉cGMP水平完全恢复正常，而仅在LPS处理大鼠中，ODQ可部分抑制cGMP水平。这些结果表明，在内毒素血症期间，非NO介质也可激活可溶性GC。有趣的是，我们发现，在存在四乙铵（一种K+通道抑制剂）加L-NAME或蝎毒素[一种大电导Ca2+激活K+（KCa）通道的特异性抑制剂]加ODQ的情况下，LPS处理组对NE的血管低反应性也完全恢复正常。此外，在存在L-NAME或ODQ的情况下，LPS处理组的主动脉环对高K+的血管低反应性被消除。这些结果表明，除了NO之外，LPS还会导致其他介质的产生，这些介质也会刺激可溶性GC（即增加cGMP的形成），然后激活血管平滑肌中的大电导KCa通道，从而导致血管低反应性。
