Vascular Biology Center, CB 3213, Medical College of Georgia, Augusta, GA 30912, USA.
Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H718-24. doi: 10.1152/ajpheart.00393.2010. Epub 2010 Dec 10.
We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H(2)O(2) and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH(4))-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH(4) therapy were studied. Both triple therapy and oral BH(4) therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH(4) levels and BH(4)-to-BH(2) ratio similar to ANG rats with BH(4) supplementation. Furthermore, triple therapy (but not oral BH(4) therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH(4) in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH(4) levels and NOS3 phosphorylation at Ser1177.
我们之前曾报道过，高血压大鼠的肠系膜小动脉中 NOS 衍生的 H₂O₂增加，而 NO/cGMP 信号减少。我们假设，通过四氢生物蝶呤（BH₄）依赖性机制来恢复小动脉中的 NO/cGMP 信号和内皮型一氧化氮合酶（NOS3；eNOS）磷酸化，降压治疗可以降低血压。为了验证这一假设，我们研究了来自正常血压大鼠（NORM）、血管紧张素 II 输注大鼠（ANG）、接受三联治疗（利血平、氢氯噻嗪和肼屈嗪）的 ANG 大鼠或接受口服 BH₄ 治疗的 ANG 大鼠的肠系膜小动脉。三联治疗和口服 BH₄ 治疗均能减轻 ANG 大鼠的收缩压升高，并使小动脉中的 NO/cGMP 信号恢复正常。三联治疗显著增加了血管 BH₄ 水平和 BH₄-BH₂ 比值，与补充 BH₄ 的 ANG 大鼠相似。此外，三联治疗（而非口服 BH₄ 治疗）显著增加了小动脉中的 GTP 环化水解酶 I（GTPCH I）活性，而对其表达没有影响。与 NORM 相比，ANG 大鼠小动脉中 NOS3 的 Ser1177 磷酸化减少，而 Ser633 和 Thr495 磷酸化则相似。三联治疗或口服 BH₄ 均可恢复 ANG 大鼠小动脉中 NOS3 的 Ser1177 磷酸化。总之，降压治疗通过增加 BH₄ 水平和 NOS3 的 Ser1177 磷酸化来调节小动脉中的 NO/cGMP 信号。
