Protective vasodilation during acid back diffusion into the rat gastric mucosa depends on activation of sensory neurons and mast cell degranulation with histamine release. We hypothesized that these two mediator systems interact, and that histamine partly exerts its effect via sensory nerves. Gastric blood flow (GBF), and luminal histamine were measured in chambered stomachs and mast cell numbers were assessed by morphometry. Ablation of sensory neurons and depletion of mast cells were produced by pretreatment with capsaicin or dexamethasone, respectively. Mucosal exposure to 1.5 M NaCl and then to pH 1.0 saline in ablated and control rats caused increased luminal histamine and reduced numbers of mast cells. The ECL cell marker pancreastatin remained unchanged. Only control rats responded with increase in GBF. Capsaicin stimulation (640 µM) of the undamaged mucosa, induced identical increase in GBF, and unchanged mast cell mass in normal and dexamethasone treated rats. The increase in GBF after topical exposure to histamine (30 mM) in rats pretreated with capsaicin, or a CGRP₁ antagonist (hCGRP_8-37), or exposed to, the calcium pore blocker ruthenium red, was less than half of that in control rats. These data suggest that mast cell derived histamine is involved in gastric vasodilation during acid back diffusion partly via sensory neurons.