Goodwill Adam G, James Milinda E, Frisbee Jefferson C
Center for Interdisciplinary Research in Cardiovascular Science, Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26505, USA.
Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1522-8. doi: 10.1152/ajpheart.00596.2008. Epub 2008 Aug 8.
This study determined if altered vascular prostacyclin (PGI(2)) and/or thromboxane A(2) (TxA(2)) production with reduced Po(2) contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po(2) under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po(2). Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI(2) production with reduced Po(2) was similar between strains, although TxA(2) production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH(2)/TxA(2) receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA(2), which competes against the vasodilator influences of PGI(2). These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA(2) production and may blunt vascular sensitivity to PGI(2).
本研究旨在确定，与瘦型 Zucker 大鼠（LZRs）相比，肥胖 Zucker 大鼠（OZRs）骨骼肌阻力小动脉在 Po₂降低时血管前列环素（PGI₂）和/或血栓素 A₂（TxA₂）生成的改变是否会导致其缺氧性扩张受损。在对照条件下 Po₂降低后，以及在抑制花生四烯酸代谢和一氧化氮合酶并减轻血管氧化应激升高的药理学干预后，对分离的股薄肌小动脉的机械反应进行评估。使用来自 OZRs 和 LZRs 的汇集动脉评估花生四烯酸代谢产物的生成，以响应 Po₂降低。两种品系的缺氧性扩张均依赖于内皮，与 LZRs 相比，OZRs 的缺氧性扩张减弱。一氧化氮合酶抑制对两种品系的缺氧性扩张均无显著影响。环氧化酶抑制显著降低了 LZRs 的缺氧性扩张，并消除了 OZRs 的反应。用聚乙二醇超氧化物歧化酶处理 OZRs 的小动脉可改善缺氧性扩张，且这种改善完全依赖于环氧化酶。尽管 OZRs 中 TxA₂生成增加，但 Po₂降低时血管 PGI₂生成在品系间相似，用聚乙二醇超氧化物歧化酶处理 OZRs 的血管可减弱这种差异。阻断 PGH₂/TxA₂受体和抑制血栓素合酶均可增加 OZR 小动脉的缺氧性扩张。这些结果表明，OZRs 骨骼肌小动脉缺氧性扩张受损的一个潜在机制可能是血管 TxA₂生成增加，其与 PGI₂的血管舒张作用相互竞争。这些结果还表明，代谢综合征中固有的血管氧化应激升高可能导致血管 TxA₂生成增加，并可能削弱血管对 PGI₂的敏感性。
