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Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance preprandial acid output, possibly through stimulation of the cephalic phase. The present study was designed to clarify the dynamics of ghrelin in H2 receptor (H2R)-null mice by genetic H2R knockout. Fifteen-week- and 54-week-old H2R-null mice and their littermates were used. After evaluating the levels of food intake and body-weight increments, mice were killed, and the plasma and gastric active and total ghrelin levels were examined by radioimmunoassay, and gastric preproghrelin mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction. Furthermore, each stomach specimen was evaluated by immunohistochemistry and transmission electron microscopy for ghrelin. The levels of food intake and body-weight gain of the H2R-null mice were higher than those of wild-type mice. The gastric pH of the 54-week-old H2R-null mice was lower than that of the 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level, and density of ghrelin-immunoreactive cells in the gastric mucosa of the H2R-null mice were significantly increased compared with those of the wild-type mice. Ghrelin-positive immunogold density seen in the electron micrograph was significantly reduced in A-like cells of the H2R-null mouse stomach. Ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in H2R-null mice, a genetic H2R knockout model. [ABSTRACT FROM AUTHOR]