Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder

Histamine H 2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H 2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H 2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H 1 receptor antagonist mepyramine (10 μM), and the H 2 receptor agonists dimaprit, impromidine and amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > amthamine > histamine > dimaprit (pD 2 values were 6.73 ± 0.04, 5.44 ± 0.07, 4.64 ± 0.04 and 3.71 ± 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and amthamine, which behaved as full agonists. All the H 2 receptor antagonists examined were able to inhibit amthamine-induced relaxation. Famotidine (pA 2 = 7.09 ± 0.26), zolantidine (pA 2 = 6.54 ± 0.11), compound SKF 92857 (pA 2 = 6.58 0.13) and aminopotentidine (pA 2 = 6.86 ± 0.06) competitively antagonised the amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations ( 1 μM, pA 2 =*6.83 ± 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration-response curve to amthamine (pK B = 7.55 ± 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 μM). In conclusion, histamine H 2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H 2 receptors in different experimental models.