Oliveira JM, Gonçalves J
Guanylate Cyclase Regulates Ileal Longitudinal Muscle Contractions Induced By Neurogenic Nitrergic Activity in the Rat. [JOURNAL ARTICLE]
Clin Exp Pharmacol Physiol 2009 Aug 4.
1. Nitrergic neurons regulate gastrointestinal (GI) activity and their dysfunction has been associated with various GI diseases. Nitric oxide (NO) typically relaxes GI smooth muscle but nitrergic contractions also occur. While guanylate cyclase is well established as mediating nitrergic GI relaxation, its role in contraction remains uncertain. 2. We used electrical field stimulation (EFS) to evoke biphasic contraction-relaxation responses in rat ileum strips (longitudinal muscle-myenteric plexus preparations), mediated by the endogenous nitrergic transmitter, under non-adrenergic non-cholinergic (NANC) conditions (1muM atropine and 4muM guanethidine). 3. All EFS responses were abolished by tetrodotoxin (1muM). NO synthase inhibition with N(omega)-nitro-L-arginine-methyl-ester (L-NAME) prevented both EFS-evoked contractions and relaxations. L-arginine reversed L-NAME inhibition, primarily restoring contractions and suggesting that these require lower nitrergic transmitter levels than relaxations. 4. Pre-exposure to sub-relaxant sodium nitroprusside concentrations selectively desensitized EFS-evoked contractions without affecting relaxations, suggesting different downstream mechanisms. Nevertheless, the selective guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) inhibited both nitrergic contraction and relaxation, evidencing that guanylate cyclase activation is required for both responses. 5. Results in the present study support the hypothesis that the endogenous nitrergic transmitter differentially regulates guanylate cyclase, leading to either contraction or relaxation depending on its levels, thus providing additional insight into the regulation of ileum contractility by nitrergic activity.
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