title: Interstitial cells of Cajal in the urethra are cGMP-mediated targets of nitrergic neurotransmission.
abstract: While interstitial cells of Cajal (ICC) in the urethra respond to nitric oxide (NO) donors by increasing cGMP, it remains unclear whether urethral ICC are functionally innervated by nitrergic nerves. We have addressed this issue in the rat and sheep urethra, where cGMP production and relaxation were compared in preparations subjected to electrical field stimulation (EFS; 2 Hz, 4 min) of nitrergic nerves or to exogenous S-nitroso-L-cysteine (SNC; 0.1 mM, 4 min). Upon EFS, cGMP immunoreactivity (cGMP-ir) was observed in both smooth muscle cells (SMC) and in spindle-shaped cells that contained c-kit and vimentin, features of ICC. Similarly, cGMP-ir was preferentially, but inconsistently, found in ICC of the outer muscle layer on exposure to SNC. We found separate functional groups of ICC within the urethra. Thus only ICC present in the muscle layers (ICC-M) but not those in the serosa (ICC-SR) and lamina propia (ICC-LP) seem to be specifically influenced by activation of neuronal NO synthase (nNOS). Thus the increase in cGMP-ir in the ICC-M induced by EFS was prevented by Nomega-nitro-L-arginine and ODQ. Urethral ICC did not express nNOS, although they were closely associated with nitrergic nerves. cGMP-ir was also present in the urothelium (in the rat but not in the sheep) and the vascular endothelium but not in neural structures, such as the nerve trunks and nerve terminals. Together, these results suggest a model of parallel innervation in which both SMC and ICC-M are effectors of nerve-released NO in the urethra.
authors.affiliation: Department of Physiology, Veterinary Faculty, Complutense University, Avda. Puerta de Hierro s/n, 28040 Madrid, Spain. angarcia@vet.ucm.es
authors.forename: Angeles
authors.initials: A
authors.lastname: García-Pascual
authors.forename: María
authors.initials: M
authors.lastname: Sancho
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Costa
authors.forename: Domingo
authors.initials: D
authors.lastname: Triguero
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D017615:Enteric Nervous System / Q000166:cytology* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D012756:Sheep; D009435:Synaptic Transmission / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D014521:Urethra / Q000294:innervation* / Q000502:physiology; D014746:Vimentin / Q000378:metabolism
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D014746:Vimentin; C017759:9-(tetrahydro-2-furyl)-adenine; D019335:Nitroarginine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019009:Proto-Oncogene Proteins c-kit; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000225:Adenine