IDENTIFICATION OF ADENYLATE-CYCLASE COUPLED HISTAMINE H-2 RECEPTORS IN GUINEA-PIG TRACHEAL SMOOTH-MUSCLE CELLS IN CULTURE AND THE EFFECT OF DEXAMETHASONE

Histamine acts on airway contractile elements through at least two different receptor subtypes: H-1, which mediates Ca2+-dependent contraction, and H-2, which stimulates cyclic adenosine monophosphate (cAMP) synthesis and possibly relaxation. The aim of this study was to determine the relative contribution of the different receptor subtypes to histamine-stimulated cAMP production by guinea pig tracheal smooth muscle (GPTSM) cells in primary culture. Histamine and N-alpha-methylhistamine induced concentration-dependent cAMP synthesis; these effects were entirely blocked by 10(-4) M cimetidine, an H-2-receptor antagonist, whereas 10(-6) M thioperamide, a selective H-3 blocker, was ineffective. The H-3 agonist, R-(alpha)-methylhistamine, did not stimulate cAMP synthesis. Triprolidine, an H-1 antagonist, did not modify histamine (10(-5) M)-stimulated cAMP synthesis. Histamine (10(-5) M) doubled [Ca2+]i in GPTSM. A 24-h pretreatment of GPTSM cells with 10(-6) M dexamethasone enhanced cAMP synthesized in response to 10(-5) M histamine and to 5 X 10(-6) M forskolin but did not significantly alter either the affinity or the binding capacity for [H-3]-tiotidine, an H-2-receptor antagonist. These results indicate that GPTSM cells in culture express H-2 but not H-3 receptors, which are linked to adenylate cyclase; their functional expression does not seem to be modulated by the concurrent activation of H-1 receptors, whose presence in GPTSM is evidenced by a histamine-stimulated increase in [Ca2+]i. The most likely site of action of dexamethasone in enhancing histamine-stimulated cAMP synthesis is at the level of adenylate cyclase since the steroid had no effect on the H-2 receptor itself.