Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
J Sex Med. 2010 Dec;7(12):3857-67. doi: 10.1111/j.1743-6109.2010.01996.x. Epub 2010 Aug 30.
Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.
We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.
Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 µg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 µg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.
Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.
AngII increased SBP (22%) and increased CC arginase activity and expression (∼twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.
p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
血管紧张素 II（AngII）可激活 p38 丝裂原活化蛋白激酶（MAPK）并提高内皮细胞的精氨酸酶活性。精氨酸酶活性的上调可通过降低一氧化氮（NO）的生物利用度而导致内皮功能障碍。然而，血管紧张素 II 在阴茎中激活的信号通路在很大程度上尚不清楚。
我们假设 p38 MAPK 的激活会增加精氨酸酶的活性，从而损害 AngII 处理的小鼠的阴茎血管功能。
雄性 C57BL/6 小鼠植入含有盐水或 AngII（42 µg/kg/h）的渗透微型泵 14 天，并在微型泵植入前 2 天开始用 p38 MAPK 抑制剂 SB 203580（5 µg/kg/天）进行共处理。测量收缩压（SBP）。使用海绵体组织进行血管功能研究以及 p38 MAPK、精氨酸酶和组成型一氧化氮合酶（NOS）的蛋白表达水平和精氨酸酶活性。
精氨酸酶的表达和活性；海绵体中磷酸化 p38 MAPK、内皮型 NOS（eNOS）和神经元型 NOS 蛋白的表达；对照和 AngII 输注小鼠海绵体中的内皮依赖性和 nitrergic 神经介导的松弛作用。
AngII 增加 SBP（22%）和海绵体精氨酸酶活性和表达（增加约两倍），并增加磷酸化 P38 MAPK 水平（增加 30%）。SB 203580 可预防这些作用。乙酰胆碱诱导的内皮依赖性 NO 介导的松弛作用明显降低，SB 203580 可预防这种作用（P <0.01）。AngII（2 周）不改变 nitrergic 功能。但是，SB 203580 可显著增加对照和 AngII 组织在较低频率下的 nitrergic 松弛作用。苯肾上腺素和电刺激引起的最大收缩反应分别增加 56%和 171%，SB 203580 处理可减弱这些反应。AngII 处理还降低了 eNOS 磷酸化 Ser-1177 与对照相比。SB 203580 的治疗可预防所有这些变化。
p38 MAPK 抑制可纠正阴茎精氨酸酶的活性并预防 AngII 引起的勃起功能障碍。
