We have studied the effects of the H3-receptor agonist (R) alpha-methylhistamine [(R) alpha-MeHA] and the H3-receptor antagonist thioperamide (Thiop) on basal- and carbachol-stimulated vascular gastrin release (GR) and somatostatin release (SR) by the isolated rat stomach. Carbachol dose-dependently stimulated and inhibited GR and SR, respectively. Maximal stimulation of GR (500 +/- 112 percent of basal; p < .01), and maximal inhibition of SR (-62 +/- 9 percent under basal; p < .01) were obtained with 1 micron carbachol. Neither (R)alpha-MeHA nor Thiop, up to 10 microns, affected GR. However, SR was dose-dependently enhanced by Thiop (25 +/- 8 percent for 10 microns). Carbachol stimulation of GR was strongly inhibited by Thiop (30 +/- 7 percent for 100 nM and 73 +/- 14 percent for 1 microgram), whereas it was potentiated by (R)alpha-MeHA. Carbachol inhibition of SR was reversed by Thiop and (R)alpha-MeHA. However, the reversal effect of (R)alpha-MeHA was prevented by the CCKB/gastrin receptor antagonist PD134308. These results support H3-receptor regulation of basal and cholinergically-stimulated GR and SR.