PnPP-19 peptide has a primary sequence design based on molecular modeling studies of PnTx2-6 toxin. It comprises the amino acid residues that are potentially significant for the pharmacological action of PnTx2-6. Ex vivo and in vivo experiments in normotensive, hypertensive, or diabetic murine models have shown a significant improvement in penile erection after administration of PnPP-19. Given the potential use of PnPP-19 in pharmaceutical formulations to treat erectile dysfunction and the lack of information concerning its mode of action, the present work investigates its activities on the nitrergic system. PnPP-19 induced a significant increase in nitric oxide (NO) and cGMP levels in corpus cavernosum (cc). These effects were inhibited by l-NAME, a non-selective inhibitor of nitric oxide synthase (NOS); were partially inhibited by 7- Nitroindazole, a selective inhibitor of neuronal NOS (nNOS); and were abolished by L-NIL, a selective inhibitor of inducible NOS (iNOS). This potentiating effect was not affected by atropine. PnPP-19 also led to changes in mRNA levels, protein expression and phosphorylation at specific sites of NOS, in cc. Assays using cavernous tissue from knockout mice to endothelial NOS (eNOS), nNOS or iNOS showed that PnPP-19 potentiates relaxation only in eNOS-knockout mice, which suggests an essential role for nNOS. Surprisingly, iNOS enhanced the potentiation of erectile function evoked by PnPP-19. Our results demonstrate that this new synthetic peptide potentiates erectile function via nitric oxide activation and reinforce its role as a new pharmacological tool for the treatment of erectile dysfunction.

PnPP-19 肽具有基于 PnTx2-6 毒素的分子模型研究的一级序列设计。它包含对 PnTx2-6 的药理作用具有潜在意义的氨基酸残基。在正常血压、高血压或糖尿病小鼠模型中的离体和体内实验表明，在施用 PnPP-19 后阴茎勃起有显着改善。鉴于 PnPP-19 在治疗勃起功能障碍的药物制剂中的潜在用途以及缺乏关于其作用方式的信息，目前的工作调查其对氮能系统的活性。PnPP-19 诱导海绵体 (cc) 中一氧化氮 (NO) 和 cGMP 水平显着增加。这些影响被l抑制-NAME，一氧化氮合酶 (NOS) 的非选择性抑制剂；被神经元 NOS (nNOS) 的选择性抑制剂 7-硝基吲唑部分抑制；并被诱导型 NOS (iNOS) 的选择性抑制剂 L-NIL 废除。这种增强作用不受阿托品的影响。PnPP-19 还导致 cc 中 NOS 特定位点的 mRNA 水平、蛋白质表达和磷酸化的变化。使用从敲除小鼠到内皮 NOS (eNOS)、nNOS 或 iNOS 的海绵组织进行的测定表明，PnPP-19 仅在 eNOS 敲除小鼠中增强松弛，这表明 nNOS 具有重要作用。令人惊讶的是，iNOS 增强了 PnPP-19 诱发的勃起功能。我们的研究结果表明，这种新的合成肽通过增强勃起功能 一氧化氮活化并加强其作为治疗勃起功能障碍的新药理学工具的作用。