Reflux esophagitis is a very common clinical disorder. Though most patients suffer with annoying """"""""heartburn"""""""", longstanding esophagitis can cause severe pain, bleeding, ulceration and stricture and in rare instances, carcinoma of the esophagus. The pathogenesis of this condition remains under investigation. Excessive exposure of the esophageal mucosa to noxious components of the gastric lake, including acid, bile, and pepsin, is clearly a major factor in producing reflux esophagitis. Little is known, however, of the mucosal protection mechanisms of the esophagus. The PI has chosen as a long-term objective to investigate the role of mucosal blood flow in esophageal mucosal protection and injury. To study this parameter, the PI has developed a method to reliably measure esophageal blood flow in rabbits using radioactive microspheres during in vivo luminal perfusion of the esophagus. The PI has observed that exposure of the esophagus to noxious luminal agents including acid, bile, and alcohol causes rapid significant increases in esophageal mucosal blood flow. These findings led to the first hypothesis: reactive augmentation of mucosal blood flow in response to noxious luminal agents is a mechanism of esophageal mucosal protection. Subsequently, the PI has shown that luminal instillation of capsaicin, a specific stimulus of chemosensitive visceral afferent neurons, causes similar striking increases in mucosal blood flow. These observations led to the second hypothesis: the chemosensitive neurons of the esophagus are the local effectors of increases in esophageal blood flow induced by noxious luminal agents. This protocol uses a well-described in vivo rabbit model of esophagitis and radioactive microsphere technique to measure esophageal blood flow to address 5 specific aims to test these hypotheses. 1: Determine the characteristics of capsaicin as a pharmacologic probe in the study of esophageal blood flow. These studies will characterize the local and systemic effects of capsaicin stimulation and sensory nerve ablation on esophageal blood flow and mucosal function. 2: Identify the neurotransmitter(s) responsible for the local blood flow changes induced by capsaicin stimulation. 3: Determine the distribution and neuropeptide content of the capsaicin sensitive nerves of the esophagus. 4: Identify the role of the sensory afferent neurons in protection against esophageal mucosal injury. In these experiments, the rabbit in vivo perfusion model of esophagitis will be used to determine if absence of sensory afferent function predisposes the esophageal mucosa to injury. 5: Determine the possible therapeutic benefit of capsaicin as a mucosal protection agent. These experiments will determine if local pre-treatment of the esophagus with capsaicin can preserve mucosal blood flow and protect the esophageal mucosa in an in vivo rabbit model of esophagitis.
