Dept. of Physiology, Seoul National University College of Medicine, 103 Daehakno, Jongnogu, Seoul 110-799, Korea.
Am J Physiol Cell Physiol. 2013 Jan 1;304(1):C78-88. doi: 10.1152/ajpcell.00176.2012. Epub 2012 Oct 24.
In contrast to the conventional belief that systemic arteries dilate under hypoxia, we found that α-adrenergic contraction of rat deep femoral artery (DFA) is largely augmented by hypoxia (HVC(DFA)) while hypoxia (3% Po(2)) alone had no effect. HVC(DFA) was consistently observed in both endothelium-intact and -denuded vessels with partial pretone by phenylephrine (PhE) or by other conditions (e.g., K(+) channel blocker). Patch-clamp study showed no change in the membrane conductance of DFA myocytes by hypoxia. The RhoA-kinase inhibitor Y27632 attenuated HVC(DFA). The nitric oxide synthase inhibitor [nitro-L-arginine methyl ester (L-NAME)] and soluble guanylate cyclase inhibitor [oxadiazole quinoxalin (ODQ)] strongly augmented the PhE-pretone, while neither of the agents had effect without pretone. NADPH oxidase type 4 (NOX4) inhibitors (diphenylene iodonium and plumbagin) also potentiated PhE-pretone, which was reversed by NO donor. No additive HVC(DFA) was observed under the pretreatment with L-NAME, ODQ, or plumbagin. Western blot and immunohistochemistry analysis showed that both NOX4 and endothelial nitric oxide synthase (eNOS) are expressed in smooth muscle layer of DFA. Various mitochondria inhibitors (rotenone, myxothiazol, and cyanide) prevented HVC(DFA). From the pharmacological data, as a mechanism for HVC(DFA), we suggest hypoxic inhibition of eNOS in myocytes. The putative role of NOX4 and mitochondria requires further investigation. The HVC(DFA) may prevent imbalance between cardiac output and skeletal blood flow under emergent hypoxia combined with increased sympathetic tone.
与传统观念相反，我们发现，在缺氧条件下，大鼠股深动脉（DFA）的系统动脉不仅不会扩张，反而会出现α肾上腺素能收缩增强（HVC（DFA）），而单纯缺氧（3%Po（2））则没有影响。HVC（DFA）在完整内皮和去内皮血管中均观察到，部分通过苯肾上腺素（PhE）或其他条件（如 K（+）通道阻滞剂）预先收缩。膜片钳研究表明，缺氧对 DFA 心肌细胞的膜电导没有影响。RhoA 激酶抑制剂 Y27632 减弱了 HVC（DFA）。一氧化氮合酶抑制剂 [硝基-L-精氨酸甲酯（L-NAME）]和可溶性鸟苷酸环化酶抑制剂 [恶二唑喹喔啉（ODQ）]强烈增强了 PhE 预收缩，而在没有预收缩的情况下，两种药物均无作用。NADPH 氧化酶 4（NOX4）抑制剂（二苯碘鎓和白花丹醌）也增强了 PhE 预收缩，NO 供体可逆转其作用。在 L-NAME、ODQ 或白花丹醌预处理下，未观察到 HVC（DFA）的附加作用。Western blot 和免疫组化分析表明，NOX4 和内皮型一氧化氮合酶（eNOS）均在 DFA 的平滑肌层表达。各种线粒体抑制剂（鱼藤酮、米唑噻唑和氰化物）可预防 HVC（DFA）。根据药理学数据，作为 HVC（DFA）的机制，我们提出缺氧抑制肌细胞中的 eNOS。NOX4 和线粒体的潜在作用需要进一步研究。在紧急缺氧合并交感神经张力增加的情况下，HVC（DFA）可能有助于防止心输出量和骨骼肌血流之间的失衡。
