Johnson Fruzsina K, Durante William, Peyton Kelly J, Johnson Robert A
Department of Physiology, Tulane University Health Sciences Center, New Orleans, La 70112, USA.
Hypertension. 2003 Jan;41(1):149-55. doi: 10.1161/01.hyp.0000046923.52222.58.
Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). CO relaxes vascular smooth muscle but inhibits nitric oxide (NO) formation. Decreased NO synthesis may contribute to salt-induced hypertension in Dahl salt-sensitive (DS) rats. The current study examines the hypothesis that elevated levels of endogenous CO contribute to NO dysfunction in salt-induced hypertensive DS rats. Male DS rats were placed on high-salt (8% NaCl, HS) or low-salt (0.3% NaCl, LS) diets for 4 weeks. With respect to the LS group, the HS group's blood pressure and carboxyhemoglobin levels were elevated, and abdominal aortas showed 6-fold higher HO-1 protein levels. Experiments used isolated pressurized first-order gracilis muscle arterioles superfused with oxygenated modified Krebs buffer. An inhibitor of NO synthase, Nomega-nitro-L-arginine methyl ester (L-NAME), caused concentration-dependent vasoconstriction in both groups, with attenuated responses in HS arterioles. HS arterioles also showed attenuated vasodilatory responses to an endothelium-dependent vasodilator, acetylcholine. Acute pretreatment with an inhibitor of HO, chromium mesoporphyrin, enhanced vascular responses to L-NAME and acetylcholine in both groups but abolished the differences between HS and LS arterioles. These data show that HO-1 protein levels and CO production are increased in HS rats. Arteriolar responses to L-NAME and acetylcholine are impaired in HS rats compared with LS animals, and this difference can be abolished by an inhibitor of endogenous CO production. These results suggest that elevated levels of endogenous CO contribute to arteriolar NO dysfunction in DS rats with salt-induced hypertension.
血管组织表达血红素加氧酶（HO），该酶可将血红素代谢生成一氧化碳（CO）。CO可使血管平滑肌舒张，但会抑制一氧化氮（NO）的生成。NO合成减少可能是导致 Dahl 盐敏感（DS）大鼠盐诱导性高血压的原因之一。本研究检验了内源性CO水平升高会导致盐诱导性高血压DS大鼠出现NO功能障碍这一假说。将雄性DS大鼠分别给予高盐（8% NaCl，HS）或低盐（0.3% NaCl，LS）饮食4周。与LS组相比，HS组的血压和羧基血红蛋白水平升高，腹主动脉的HO-1蛋白水平高出6倍。实验采用分离的带压力的一级股薄肌肌性小动脉，用含氧的改良 Krebs 缓冲液进行灌流。NO合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME）在两组中均引起浓度依赖性血管收缩，HS小动脉的反应减弱。HS小动脉对内皮依赖性血管舒张剂乙酰胆碱的舒张反应也减弱。用HO抑制剂中卟啉铬进行急性预处理，增强了两组对L-NAME和乙酰胆碱的血管反应，但消除了HS和LS小动脉之间的差异。这些数据表明，HS大鼠的HO-1蛋白水平和CO生成增加。与LS大鼠相比，HS大鼠小动脉对L-NAME和乙酰胆碱的反应受损，而内源性CO生成抑制剂可消除这种差异。这些结果表明，内源性CO水平升高会导致盐诱导性高血压DS大鼠的小动脉NO功能障碍。
