Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo

被引:248
作者
Motterlini, R [1 ]
Gonzales, A
Foresti, R
Clark, JE
Green, CJ
Winslow, RM
机构
[1] Northwick Pk Inst Med Res, Dept Surg Res, Vasc Biol Unit, Harrow HA1 3UJ, Middx, England
[2] Univ Calif San Diego, Dept Med, Vet Adm Med Ctr, La Jolla, CA 92093 USA
关键词
surgical stress; hemoglobin-based blood substitute; carbon monoxide; bilirubin; cGMP;
D O I
10.1161/01.RES.83.5.568
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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) alpha alpha Hb, a chemically modified hemoglobin known to scavenge NO, and (2) N-G-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries ansi veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of aa Hb 18% solution) or L-NAME (30 mmol/kg) 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 aaHb 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 LX (50 mu mol/kg TP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both alpha alpha Hb 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.
引用
收藏
页码:568 / 577
页数:10
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