Effect of caffeine on tone and intracellular Ca++ release in guinea-pig and human trachealis

High concentrations of methylxanthines induce contraction in many smooth muscle types, but relax guinea-pig trachealis. We examined this discrepancy by studying the interaction of caffeine and spasmogens in the isolated guinea-pig trachealis. We extended our observations to the isolated human trachealis. In the guinea-pig trachealis, 25 mM but not 2.5 mM caffeine totally blocked any contractile effect of methacholine or histamine, but not of KCl, whose contractile effect relies on extracellular Ca++. The beta-adrenergic agent isoprenaline (10(-3)M) only partially blocked the spasmodic effect of methacholine and histamine. In the human trachealis, 25 mM but not 2.5 mM caffeine induced an initial contraction followed by a relaxation. After this latter relaxation, methacholine (10(-5) M) and histamine (10(-5) M) were without effect, while KCl caused a contraction. In the guinea-pig, a contractile effect of 25 mM but not 2.5 mM caffeine was uncovered by switching to a high K+, Ca(++)-free solution prior to adding the caffeine. The source of the Ca++ promoting the contraction thus must be intracellular stores. Accordingly, ryanodine, an inhibitor of Ca++ storage, blocked this contraction. Similarly histamine (10(-5) M) and methacholine (10(-5) M) in the Ca(++)-free solution induced a contraction. The histamine contraction was completely blocked by ryanodine, the methacholine contraction, 79% blocked. We conclude that caffeine appears to surpass the antispasmodic effects of beta-adrenergic stimulation, at least in part, by depleting intracellular stores of Ca++.