Direct effects of H2-receptor antagonists on airway smooth muscle and on responses mediated by H1- and H2-receptors.
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 histamine (10(-5)M), dose-response curves for relaxation were shifted to the right, and low-concentrations of all three histamine H2-antagonists augmented histamine-induced tone. When preparations were pretreated with cimetidine (10(-6) to 10(-4) 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 (greater than or equal to 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.
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D015738:Famotidine; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D011899:Ranitidine / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects*
D006635:Histamine H2 Antagonists; D013844:Thiazoles; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine