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Loss of nitrergic neurotransmission to mouse corpus cavernosum in the absence of neurturin is accompanied by increased response to acetylcholine
Author(s) -
Nangle Matthew R,
Keast Janet R
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706760
Subject(s) - endocrinology , medicine , acetylcholine , knockout mouse , nitric oxide , guanethidine , phenylephrine , nitric oxide synthase , sodium nitroprusside , cholinergic , glial cell line derived neurotrophic factor , chemistry , biology , neurotrophic factors , stimulation , receptor , blood pressure
1 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 α (GFR α )2, they are capable of erection and reproduction. 2 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. 3 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. 4 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. 5 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. 6 Parallel immunohistochemical and pharmacological studies in GFR α 2 knockout animals showed the same changes from their wild types as the NTN knockout animals. 7 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.British Journal of Pharmacology (2006) 148 , 423–433. doi: 10.1038/sj.bjp.0706760