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BDNF augments rat internal anal sphincter smooth muscle tone via RhoA/ROCK signaling, and non-adrenergic, non-cholinergic relaxation via increased NO release.

Presently, there are no studies examining the neuromodulatory effects of brain-derived neurotropic factor (BDNF) on the basal internal anal sphincter (IAS) tone and non-adrenergic, non-cholinergic (NANC) relaxation. To examine this, we determined the neuromuscular effects of BDNF on basal IAS-smooth muscle tone and the smooth muscle cells (SMCs), and NANC nerve stimulation, before and after high-affinity receptor tyrosine kinase B (TrkB) antagonist K252a. We also investigated the mechanisms underlying BDNF-augmented increase in the IAS tone and NANC relaxation. We found that BDNF increased IAS tone and SMC contractility were tetrodotoxin (TTX)-resistant and attenuated by K252a. TrkB-specific agonist 7,8-dihydroxyflavone, similar to BDNF, also produced a concentration-dependent increase in the basal tone, while TrkB inhibitors K252a and ANA-12 produced a decrease in the tone. In addition, BDNF produced left-ward shifts in the concentration-response curves (CRCs) with U46619 and AngII (but not with bethanechol and K+ -depolarization), and these shifts were reversed by K252a. Effects of Y27632 and Western blot data indicated that the BDNF-induced increase in IAS tone was mediated via RhoA/ROCK. BDNF-augmented NANC relaxation by electrical field stimulation (EFS) was found to be mediated via the NO/soluble guanylate cyclase (sGC) pathway, rather than via increased sensitivity to NO. In conclusion, the net effect of BDNF was it caused an increase in the basal IAS tone via RhoA/ROCK signaling. BDNF also augmented NANC relaxation via NO/sGC. These findings may have relevance to the role of BDNF in the pathophysiology and therapeutic targeting of the IAS-associated rectoanal motility disorders.

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