Submitted on May 9, 2008
Revised on June 20, 2008
Accepted on July 11, 2008
INTERSTITIAL CELLS OF CAJAL IN THE URETHRA ARE CYCLIC GMP-MEDIATED TARGETS OF NITRERGIC NEUROTRANSMISSION
Angeles Garcia-Pascual1*, Maria Sancho2, Gonzalo Costa2, and Domingo Triguero3
1 Veterinary Faculty. Complutense University
2 Veterinary Faculty, Complutense University
3 Veterinary School. Complutense University
* To whom correspondence should be addressed. E-mail: angarcia{at}vet.ucm.es.
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 Nw-nitro-L-arginine and ODQ. Urethral ICC did not express nNOS, although they were closely associated to 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.
