Caffeine acting on pregnant rat myometrium: analysis of its relaxant action and its failure to release Ca2+ from intracellular stores

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Abstract
1 The effect of caffeine on mechanical activity was studied in pregnant rat myometrium. 2 In muscle cells with intact plasmalemmae, caffeine (0.1–50 mm) produced no contraction whatever the experimental conditions. 3 Caffeine (0.1–10 mm) inhibited, in a concentration-dependent manner, contractions induced by electrical stimulation, potassium-rich (60 mm K+) solution, sodium-free solution or oxytocin (22.5 nm). 4 In Ca2+-free solution, various substances (oxytocin, sodium orthovanadate and prostaglandin E2) evoked sustained contractions that were suppressed by caffeine (5–10 mm). When caffeine (> 5 mm) was applied during Ca2+-loading of the tissue (2.1 mm Ca2+, 5 min) in the presence of a K+-rich solution, the subsequent transient contraction induced by a short application (10 s) of oxytocin (22.5 nm) in Ca-free solution was reduced (63 ± 3.5% reduction for 20 mm caffeine, n = 4). 5 In saponin-skinned strips, application of caffeine (5–10 mm) during loading of the Ca2+-store increased the subsequent contraction induced by myo-inositol 1,4,5 trisphosphate (IP3, 10 μm). Caffeine (10–30 mm) decreased calcium-activated contractions in skinned fibres lacking a functional internal Ca-store. This effect was reduced by the cyclic AMP-dependent protein kinase inhibitor Thr-Thr-Tyr-Ala-Asp-Phe-Ile-Ala-Ser-Gly-Arg-Thr-Gly-Arg-Arg-Asn-Ala-Ile-His-Asp (8 μm). 6 In conclusion, it is suggested that the inability of caffeine to cause spasm of rat myometrium is due to the absence of a caffeine-sensitive calcium-release channel in the sarcoplasmic reticulum. Relaxant effects of caffeine can be explained by mechanisms leading to a decrease in both the cytoplasmic free Ca2+ concentration and the Ca2+-sensitivity of the contractile machinery.