Motterlini R, Gonzales A, Foresti R, Clark J E, Green C J, Winslow R M
Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK.
Circ Res. 1998 Sep 7;83(5):568-77. doi: 10.1161/01.res.83.5.568.
The enzyme heme oxygenase, which exists in inducible (HO-1) and constitutive (HO-2) isoforms, catalyzes the degradation of heme to biliverdin and CO in mammalian tissues. CO has been implicated in the control of vascular tone in a manner similar to that for NO. In the present study, we investigated the contribution of the heme oxygenase/CO pathway to the modulation of acute hypertensive responses in vivo induced by (1) alphaalphaHb, a chemically modified hemoglobin known to scavenge NO, and (2) NG-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries and veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of alphaalphaHb (8% solution) or L-NAME (30 micromol/kg) [corrected] produced an acute and significant increase in mean arterial pressure (P<0.05) in rats at 5 days after catheter implantation. In contrast, no change in blood pressure was observed when alphaalphaHb or L-NAME was infused 1 day after the surgical intervention. The suppression of the hypertensive response observed at 1 day after surgery correlated with a significant (P<0.05) HO-1 expression in aorta, heart, and liver as well as increased aortic CO production and cGMP levels. At 1 day after surgery, pretreatment of animals with the heme oxygenase inhibitor zinc protoporphyrin IX (50 micromol/kg IP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both alphaalphaHb and L-NAME. These results provide evidence for a crucial role of the heme oxygenase/CO pathway in the regulation of blood pressure under stress conditions in vivo.
血红素加氧酶存在诱导型（HO - 1）和组成型（HO - 2）两种同工型，可催化哺乳动物组织中血红素降解为胆绿素和一氧化碳。一氧化碳与一氧化氮类似，参与血管张力的调控。在本研究中，我们探究了血红素加氧酶/一氧化碳途径对体内急性高血压反应调节的作用，该反应由以下两种物质诱导产生：（1）ααHb，一种已知可清除一氧化氮的化学修饰血红蛋白；（2）NG - 硝基 - L - 精氨酸甲酯（L - NAME），一种竞争性一氧化氮合酶抑制剂。实验在清醒大鼠中进行，在使用血管收缩剂治疗前1天或5天，通过手术将导管插入大鼠股动脉和静脉。静脉输注ααHb（8%溶液）或L - NAME（30微摩尔/千克）[校正后]可使导管植入后5天的大鼠平均动脉压急性显著升高（P<0.05）。相比之下，在手术干预后1天输注ααHb或L - NAME时，未观察到血压变化。手术1天后观察到的高血压反应抑制与主动脉、心脏和肝脏中显著的（P<0.05）HO - 1表达以及主动脉一氧化碳生成和环鸟苷酸水平升高相关。在手术后1天，用血红素加氧酶抑制剂锌原卟啉IX（50微摩尔/千克腹腔注射）预处理动物，可显著降低主动脉一氧化碳和环鸟苷酸水平，并完全恢复ααHb和L - NAME的血管收缩作用。这些结果为血红素加氧酶/一氧化碳途径在体内应激条件下血压调节中的关键作用提供了证据。
