Inhibitory effects of caffeine on contractions and calcium movement in vascular and intestinal smooth muscle

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Abstract
1 The mechanism of the inhibitory effect of caffeine was investigated using vascular smooth muscle of rabbit aorta and intestinal smooth muscle of taenia isolated from guinea-pig caecum. 2 Caffeine, 0.5–10 mm, relaxed the sustained contraction induced by 65.4 mm KCl or 10−6 m noradrenaline in aorta, and by 45.4 mm KCl or 10−6 m carbachol in taenia. The inhibitory effect of caffeine on the high K+-induced contraction was antagonized by external Ca2+ but not by the Ca2+ channel activators, Bay K 8644 (10−7 m) or CGP 28,392 (10−7 m). Forskolin (2 × 10−7 m) potentiated the inhibitory effect of caffeine on the noradrenaline-induced contraction but not on the high K+- or carbachol-induced contraction. Caffeine induced a time-and concentration-dependent increase in the cyclic AMP content of aorta and forskolin caused a further augmentation. 3 45Ca2+ uptake was increased by high K+ or noradrenaline in aorta and by high K+ or carbachol in taenia. The increments were inhibited by caffeine at concentrations needed to inhibit muscle contractions. 4 45Ca2+ in the cellular releasable site in aorta was decreased either by noradrenaline or by caffeine. Simultaneous application of noradrenaline and caffeine did not induce an additive decrease. 5 In aorta treated with a Ca2+-free solution, caffeine induced only a small contraction. Noradrenaline induced a greater contraction which was inhibited by caffeine. After washout of caffeine and noradrenaline, the second application of noradrenaline induced a transient contraction suggesting that caffeine does not deplete the noradrenaline-sensitive store. Caffeine did not inhibit Ca2+ accumulation by the noradrenaline-sensitive store. 6 It was concluded that caffeine has multiple sites of action in smooth muscle. Caffeine releases Ca2+ from a store which is apparently not sensitive to noradrenaline. Caffeine may inhibit noradrenaline-induced Ca2+ release. Caffeine itself induces only a small contraction possibly because it decreases the Ca2+ sensitivity of contractile filaments and/or increases Ca2+ extrusion. Further, caffeine seems to inhibit stimulated Ca2+ influx. Cyclic AMP may be only partly responsible for the inhibitory effect of caffeine.