Question:

Esophageal achalasia is known to result from impairment of nonadrenergic noncholinergic (NANC) nerves. In addition to VIP and ATP, NO is one of the main NANC transmitters. To date, the exact mechanism of nitric oxide (NO)-induced smooth muscle relaxation in the gastrointestinal tract is still controversial. NO-sensitive guanylyl cyclase (NO-GC) acts as the main target of NO and has been demonstrated to be the important physiological mediator of nitrergic relaxation in the lower esophageal sphincter (LES).

Methods:

Recently, we have generated mice lacking NO-GC (GCKO). We have shown that a lack of NO-GC results in the impairment of GI motility concomitant with an abolished NO responsiveness of gastrointestinal smooth muscle. The role of NO-GC in different gastrointestinal cells for LES relaxation was assessed using cell-specific knockout mouse lines lacking NO-GC in smooth muscle cells (SM-GCKO) and interstitial cells of Cajal (ICC-GCKO) as well as in both cell types (SM/ICC-GCKO). Esophageal manometry was used to study the functionality of the LES in the cell-specific knockouts in vivo. Isometric force studies were performed to monitor the responsiveness towards exogenous NO.

Results:

Only in double knockouts (SM/ICC-GCKO) we observed a phenotype similar to that seen in total GCKO mice including lack of nitrergic relaxation and increased basal tone of LES.

Conclusions:

In the present study we show that the nitrergic inhibitory neurotransmission in LES underlies a dual mechanism which is mediated by NO-GC in at least two cell types (SMC and ICC).