Direct Effects of H2-Receptor Antagonists on Airway Smooth Muscle and on Responses Mediated by H1- and H2-Receptors

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Abstract
Because it has been suggested that histamine H2-receptor antagonists may worsen airway constriction in asthmatic patients, we investigated the comparative effects of three histamine H2-receptor antagonists on guinea pig tracheal smooth muscle in vitro. When tested against resting tone, cimetidine, ranitidine and famotidine produced dose-related relaxation with pD2 values (negative log of ED50 for relaxation) (.+-. SE, n; eq 5) of 3.20 .+-. 0.04, 2.95 .+-. 0.16 and 2.97 .+-. 0.14, respectively. Concentrations that were below threshold for relaxation, did not elicit contraction. However, when the preparations were precontracted with cimetidine (10-6 to 10-6 M) and then tested for sensitivity to histamine, dose-response curves for histamine-induced contraction were shifted to the left (potentiated). These results provide further evidence for a modulatory effect of airway H2-receptors on the contractile response to histamine. In addition, since the concentrations associated with potentiation of histamine-induced contraction were about the same for all three H2-receptor antagonists (.gtoreq. 10-5 M), our studies suggest a greater likelihood of airway constriction for the less potent H2-receptor antagonists that must be administered in higher clinical doses.