Decrease of guanylyl cyclase β1 subunit and nitric oxide (NO)-induced relaxation in mouse rectum with colitis and its reproduction on long-term NO treatment

Abstract

Nitric oxide (NO) influences motility in the colon in patients with ulcerative colitis, but the exact mechanism involved remains unknown. Colitis was induced in mice by the oral administration of 2.5% dextran sodium sulfate (DSS), and the motility in longitudinal preparations from rectum and distal colon and expression of β1 subunit of soluble guanylyl cyclase (sGCβ1) were analyzed. Electrical stimulation (ES) caused a transient relaxation via the NO pathway in both rectum and colon from control mice. Stimulation with sodium nitroprusside (SNP) caused relaxation in the two regions, and the half-time (T (1/2)) of the maximal relaxation induced by 100 μM SNP was 8.1 ± 1.0 s in rectum. DSS treatment (1) abolished the ES-induced relaxation, but not dibutyryl cyclic GMP-induced response, in both regions, (2) decreased the maximal response to SNP accompanied by a loss of immunoreactive sGCβ1 protein in rectum, but did not affect the amplitude of the relaxant response or the protein in distal colon, and (3) caused an increase in the T (1/2) value in response to SNP in both regions. Pretreatment of both preparations from control mice with 600 μM SNP for 30 min decreased both ES- and SNP-induced relaxation, SNP-induced cyclic GMP formation, and immunoreactive sGCβ1 levels. NO-mediated relaxation was impaired by a dysfunctional sGC with and without a loss of immunoreactivity to sGCβ1 in rectum and colon from DSS-treated mice, respectively. Long-term exposure of the tissues with an excess amount of NO changes the sGC-mediated relaxation.

Influence of cinaciguat on gastrointestinal motility in apo‐sGC mice

“…It can be expected that these conditions can lead to oxidation of the heme‐group in enteric sGC; this will induce heme‐free sGC, contributing to reduced effectiveness of the NO/sGC/cGMP pathway. Decreased sensitivity of sGC was reported in DSS‐induced colitis in mice and rats . Cinaciguat might thus be able to activate sGC in this type of gastrointestinal disorders, possibly improving gastrointestinal dysmotility.…”