Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter

Key points Nitric oxide (NO) is an important inhibitory neurotransmitter in the gastrointestinal tract. Oesophageal achalasia may result from impairment of nitrergic relaxation. Smooth muscle cells (SMCs) have been accepted to be the major targets for neuronal NO to mediate relaxation. However, besides SMCs, the receptor for NO, NO‐sensitive guanylyl cyclase (NO‐GC), has been shown in interstitial cells of Cajal (ICC). Using cell‐specific knockout mice, this study shows that NO‐GC in SMC and ICC modulates lower oesophagus sphincter tone in vitro and in vivo. More importantly, NO‐GC in ICC possesses a dominant role in mediating swallowing‐induced relaxation. Lack of functional nitrergic signalling, thus, results in deficits in relaxation of the lower oesophagus sphincter as seen in achalasic patients. Oesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO‐sensitive guanylyl cyclase (NO‐GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO‐GC in LES relaxation, we used cell‐specific knockout (KO) mouse lines for NO‐GC. These include mice lacking NO‐GC in smooth muscle cells (SMC‐GCKO), in interstitial cells of Cajal (ICC‐GCKO) and in both SMC/ICC (SMC/ICC‐GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell‐specific expression/deletion of NO‐GC was monitored by immunohistochemistry. Swallowing‐induced LES relaxation is strongly reduced by deletion of NO‐GC in ICC. Basal LES tone is affected by NO‐GC deletion in either SMC or ICC. Lack of NO‐GC in both cells leads to a complete interruption of NO‐induced relaxation and, therefore, to an achalasia‐like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO‐GC in SMC and ICC whereas swallow‐induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.