Dr. Hiroshi Mashimo is the Chief of Gastroenterology in the VA Boston Healthcare System. His research interests lie in examining the roles of nitric oxide and vasoactive intestinal peptide in gastrointestinal neurotransmission. Nitric oxide (NO) and vasoactive intestinal peptide (VIP) are implicated in a variety of gastrointestinal functions, including mucosal protection, gastric acid secretion, hepatic regulation of blood flow, and gastrointestinal motility. The last entails an orchestrated series of contractions and relaxations mediated in part by NO and VIP via nonadrenergic noncholinergic (NANC) nerves. Early studies have been limited by available pharmacologic agents which are often transient, non-specific, and non-uniform in their action. Thus, whole mice with genetically targeted disruptions represent exciting and uniquely suited models for the study of putative neurotransmitters. Mice genetically incapable of expressing either the neuronal or endothelial forms of constitutive nitric oxide synthase (nNOS and eNOS, respectively) have been generated by gene-targeted disruption. Mice lacking the nNOS develop enlarged stomach and hypertrophy of the pylorus reminiscent of hypertrophic pyloric stenosis in humans. Using these mutant mice, Dr. Mashimo’s group have shown the antegrade neurotransmitter role of nitric oxide and its enzymatic source in eventuating smooth muscle relaxation, and have established the intermediary role for VIP. They are presently defining physiological effects of nNOS and eNOS deprivation by electrophysiological and mechanical assays, and are uncovering the cellular signaling pathway of nitric oxide action. The laboratory is also studying novel methods of local gene delivery in the gastrointestinal tract using these animal models, which may have important applicability in treating human conditions. These studies will begin to address the long-range goal of understanding the complex interaction of hormones and neurotransmitters in gastrointestinal physiology and will hopefully lead to understanding and possible treatment of such conditions as Hirschsprung's disease, Chagas disease, achalasia, and pyloric stenosis that are associated with deficiency of nitric oxide production.
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