An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice
An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice
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DOI：
10.1073/pnas.97.17.9747
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发表时间：
2000-08-15
影响因子：
11.1
通讯作者：
Busse, R
中科院分区：
文献类型：
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作者：
Brandes, RP;Schmitz-Winnenthal, FH;Busse, R
除了一氧化氮（NO）和前列环素（PG 1（2））外，内皮还产生内皮源性超极化因子（EDHF）。我们着手确定是否可以在野生型（WT）和内皮NO合酶敲除小鼠（eNOS -/-）小鼠中检测到EDHF样反应。在体内和体外测定血管舒张剂对内皮依赖性激动剂的反应。在体内，缓激肽诱导平均动脉压（MAP）显著的剂量依赖性降低，WT和eNOS -/-小鼠之间没有差异，并且不受N-ω-硝基-L-精氨酸甲酯和双氯芬酸治疗的影响。在WT和eNOS -/-小鼠的盐水灌注后肢中，观察到对缓激肽和乙酰胆碱（ACh）的反应明显的N-ω-硝基-L-精氨酸（L-NA，300 μ mol/L）-和双羟萘酸-不敏感的血管舒张，这比在没有L-NA的情况下WT后肢中激动剂诱导的血管舒张更明显。这种内皮依赖性、NO/PG 1（2）非依赖性的血管舒张作用对KCl（40 mM）以及蜂毒肽和Charybdotoxin的组合敏感。帽连接抑制剂（18 α-大黄酸，辛醇，庚醇）和CB-1大麻素受体激动剂（Δ 9-四氢大麻酚，HU 210）损害EDHF介导的血管舒张，而细胞色素P450酶，可溶性鸟苷酸环化酶，或腺苷受体的抑制对EDHF介导的反应没有影响。这些结果表明，在小鼠阻力血管中，体内和体外主要激动剂诱导的内皮依赖性血管舒张不是由NO、PG 1（2）或细胞色素P450代谢物介导的，而是由需要功能性间隙连接的EDHF样原理介导的。
In addition to nitric oxide (NO) and prostacyclin (PGl(2)) the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N-omega-nitro-L-arginine methyl ester and diclofenac. In the saline-perfuse hindlimb of WT and eNOS -/- mice, marked N-omega-nitro-L-arginine (L-NA, 300 mu mol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonistinduced vasodilation in the hindlimb of WT in the absence of L-NA. This endothelium-dependent, NO/PGl(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Cap junction inhibitors (18 alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta 9-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGl(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions.