Effects of Alkylxanthines on Contractility of Diaphragm Fibres Isolated from Normal and Sensitized Guinea-pigs

Abstract

Abstract This study investigates the effects of alkylxanthines on twitch tension generated by electrical stimulation (supramaximal pulses, 0·2 ms duration, 1 Hz) of diaphragm muscle fibres isolated from normal and actively-sensitized guinea-pigs. Caffeine, theophylline and theobromine increased, in a concentration-dependent manner (50–500 μm), twitch tension in normal and sensitized diaphragm. Caffeine (500 μm) enhanced contractility to a greater extent than theophylline or theobromine. Twitch potentiation by caffeine (500 μm) was significantly greater in sensitized diaphragm. Verapamil (0·1–100 μm) did not alter twitch contractions in the absence or presence of alkylxanthines in normal or sensitized strips. Dantrolene (0·01–100 μm) depressed, in a concentration-dependent fashion, twitch contractions of normal and sensitized diaphragm. The inhibitory concentration 50% (expressed as —log IC50) was 6·78 ± 0·13 in normal tissues and 6·15 ± 0·11 in sensitized tissues (n = 6 in each group; P < 0·05). Exposure to Ca2+-free, EGTA (0·1 Mm)-containing medium, depressed twitch contraction of normal diaphragm to a lesser extent than that of sensitized diaphragm. Methylxanthines reversed depression of twitch contractions produced by exposure to dantrolene (5 μm) or a Ca2+ -free medium. Adenosine (1–1000 μm) was without effect whereas enprofylline (50–500 μm) enhanced diaphragm contractility in normal tissues. This indicates that blockade of adenosine receptors is not involved in the inotropic effect of alkylxanthines in guinea-pig diaphragm. Results from this study suggest that alkylxanthines enhance diaphragm contractility in the guinea-pig by releasing intracellular Ca2+ and promoting extracellular Ca2+ entry through verapamil-insensitive pathways. An alteration of Ca2+ movements and stores may be present in the sensitized diaphragm.