The nitric oxide and renin-angiotensin II systems in the human esophagus

Abstract

The primary function of the esophagus is to transport food boluses from the oral cavity to the stomach. Secondary functions are to prevent retrograde movements of the acidified gastric contents, but also to allow evacuation of gas. Well co-ordinated muscular activity and mucosa-protective mechanisms are thus pivotal for optimal esophageal functionality. Local mediators as well as central neural reflexes are operational alone or in combination. The general aim of the present thesis was to investigate two previously less studied regulatory systems in the human esophagus: juxtamucosal NO formation and the renin-angiotensin system (RAS). Examinations of esophageal mucosa and motor activity in vivo were performed on healthy volunteers. Specimens of the esophageal musculature with confirmed normal appearance were obtained from patients undergoing esophagogastric resection. Juxtamucosal NO formation was assessed using a tonometric technique. Salivary volume and titrable alkalinity were used to calculate alkaline secretion. Esophageal smooth muscle contractions in response to angiotensin II were studied using an organ-bath. Contractile events of the distal esophagus in vivo were assessed using multiple recordings of hydrostatic pressure and potential difference along a nasogastric catheter. Immunohistochemistry, PCR and the Western blotting were used to detect NO synthases and components of RAS.The results demonstrate that two sources exist for the esophageal luminal NO formation; chemical reduction of salivary nitrite and enzymatic degradation of L-arginine in the epithelium, both dependent on the presence of acid in the esophageal lumen. Salivary alkaline secretion increased markedly following intraluminal acid exposure and data suggest that intraluminal NO facilitates initiation of the acid-induced esophago-salivary reflex. Mucosal biopsies and muscular tissue both indicate the existence of a local renin-angiotensin system in the normal human esophagus. Angiotensin II stimulates the human distal esophageal musculature in vitro via the AT1 receptor subtype, and administration of the AT1 receptor antagonist candesartan reduces the amplitude of swallows-induced peristaltic contractions and the length of the high-pressure zone in vivo.In conclusion, the investigations show that both juxtamucosal NO formation and a local RAS exist in the human esophagus, and that both these regulatory systems are functional during physiological conditions.