title: Effects of alkylxanthines on contractility of diaphragm fibres isolated from normal and sensitized guinea-pigs.
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 microM), twitch tension in normal and sensitized diaphragm. Caffeine (500 microM) enhanced contractility to a greater extent than theophylline or theobromine. Twitch potentiation by caffeine (500 microM) was significantly greater in sensitized diaphragm. Verapamil (0.1-100 microM) did not alter twitch contractions in the absence or presence of alkylxanthines in normal or sensitized strips. Dantrolene (0.01-100 microM) 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 Ca(2+)-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 microM) or a Ca(2+)-free medium. Adenosine (1-1000 microM) was without effect whereas enprofylline (50-500 microM) 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
authors.forename: J D
authors.initials: JD
authors.lastname: Orón
authors.forename: J
authors.initials: J
authors.lastname: Cortijo
authors.forename: M
authors.initials: M
authors.lastname: Perpiñá
authors.forename: E J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D003470:Culture Media; D003620:Dantrolene / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007114:Immunization; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013805:Theobromine / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D001993:Bronchodilator Agents; D003470:Culture Media; D014970:Xanthines; D012710:Serum Albumin, Bovine; D002110:Caffeine; D013806:Theophylline; D014700:Verapamil; C034347:enprofylline; D003620:Dantrolene; D000241:Adenosine; D013805:Theobromine; D002118:Calcium