Nangle Matthew R, Keast Janet R
Pain Management Research Institute, Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Br J Pharmacol. 2006 Jun;148(4):423-33. doi: 10.1038/sj.bjp.0706760. Epub 2006 May 8.
The neurotrophic factor, neurturin (NTN), plays an important role in parasympathetic neural development. In the penis, parasympathetic nitrergic/cholinergic nerves mediate the erectile response. However, despite reduced parasympathetic penile innervation in mice lacking the NTN receptor, glial cell line-derived neurotrophic factor family receptor alpha (GFRalpha)2, they are capable of erection and reproduction. Our aim was to assess neural regulation of erectile tissues from mice lacking NTN. Responses of cavernosal smooth muscle were studied in vitro, monitoring agonist- and nerve-evoked changes in tension. Frequency-dependent nerve-evoked relaxations in the presence of guanethidine were markedly reduced in the mutant mice compared to wild types (19 vs 72% of phenylephrine pre-contraction). Atropine reduced the amplitude in wild-type mice to 61%, but abolished relaxations in knockout mice. In wild-type and knockout animals, nitric oxide synthase inhibition abolished neurogenic relaxations. In NTN knockout animals, EC(50) values for nitric oxide-dependent relaxations to acetylcholine and muscarine were increased approximately 0.5 log units. In contrast, contractions to electrical stimulation or phenylephrine, and relaxations to bradykinin or the nitric oxide donor, sodium nitroprusside, were unaltered. Immunohistochemistry confirmed that nerves immunoreactive for nitric oxide synthase, vesicular acetylcholine transporter and vasoactive intestinal polypeptide were substantially reduced in cavernosum of NTN knockout mice. Parallel immunohistochemical and pharmacological studies in GFRalpha2 knockout animals showed the same changes from their wild types as the NTN knockout animals. The data demonstrate that NTN is essential for normal development of penile erection-inducing nerves and that its absence leads to increased responsiveness to muscarinic agonists, possibly as a compensatory mechanism.
神经营养因子纽酪氨酸（NTN）在副交感神经发育中起重要作用。在阴茎中，副交感神经一氧化氮能/胆碱能神经介导勃起反应。然而，尽管缺乏NTN受体胶质细胞源性神经营养因子家族受体α（GFRalpha）2的小鼠副交感神经阴茎神经支配减少，但它们仍能够勃起和繁殖。我们的目的是评估缺乏NTN的小鼠勃起组织的神经调节。在体外研究海绵体平滑肌的反应，监测激动剂和神经诱发的张力变化。与野生型相比，突变小鼠在胍乙啶存在下频率依赖性神经诱发的舒张明显降低（去氧肾上腺素预收缩的19%对72%）。阿托品使野生型小鼠的舒张幅度降低至61%，但消除了基因敲除小鼠的舒张。在野生型和基因敲除动物中，一氧化氮合酶抑制消除了神经源性舒张。在NTN基因敲除动物中，一氧化氮依赖性舒张对乙酰胆碱和毒蕈碱的EC（50）值增加了约0.5个对数单位。相比之下，对电刺激或去氧肾上腺素的收缩以及对缓激肽或一氧化氮供体硝普钠的舒张未改变。免疫组织化学证实，NTN基因敲除小鼠海绵体中对一氧化氮合酶、囊泡乙酰胆碱转运体和血管活性肠肽免疫反应的神经明显减少。对GFRalpha2基因敲除动物进行的平行免疫组织化学和药理学研究显示，与NTN基因敲除动物一样，它们与野生型相比有相同的变化。数据表明，NTN对阴茎勃起诱导神经的正常发育至关重要，其缺失可能导致对毒蕈碱激动剂的反应性增加，这可能是一种补偿机制。
