Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hype remia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomach s were exposed to 1.5 M NaCl and acidic saline after treatment with SP, apr otinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Do ppler flow velocimeter) after hypertonic injury and acid challenge was near ly abolished by SP. Aprotinin infused together with SP and pretreatment wit h ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data s uggest that impaired hyperemia by SP during acid challenge of the gastric m ucosa may be mediated by a mast cell-dependent mechanism involving the rele ase of proteases from mast cells.