title: Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle.
abstract: It was hypothesized that the caffeine derivative paraxanthine results in subcontracture increases in intracellular calcium concentration ([Ca(2+)](i)) in resting skeletal muscle. Single fibers obtained from mouse flexor digitorum brevis were loaded with a fluorescent Ca(2+) indicator, indo 1-acetoxymethyl ester. After a stable baseline was recorded, the fiber was superfused with physiological salt solution (Tyrode) containing 0.5, 1.0, 2.5, or 5 mM paraxanthine, resulting in [Ca(2+)](i) increases of 6.4 +/- 2.5, 9.7 +/- 3.6, 26.8 +/- 11.7, and 39.6 +/- 9.6 nM, respectively. The increases in [Ca(2+)](i) were transient and were also observed with exposure to 5 mM theophylline and theobromine. Six fibers were exposed to 5 mM paraxanthine followed by 5 mM paraxanthine in the presence of 10 mM procaine (sarcoplasmic reticulum Ca(2+) release channel blocker). There was no increase from baseline [Ca(2+)](i) when fibers were superfused with paraxanthine and procaine, suggesting that the sarcoplasmic reticulum is the primary Ca(2+) source in the paraxanthine-induced response. In separate experiments, intact flexor digitorum brevis (n = 13) loaded with indo 1-acetoxymethyl ester had a significant increase in [Ca(2+)](i) with exposure to 0.01 mM paraxanthine. It is concluded that physiological and low pharmacological concentrations of paraxanthine result in transient, subcontracture increases in [Ca(2+)](i) in resting skeletal muscle, the magnitude of which is related to paraxanthine concentration.
authors.affiliation: Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1. thomas.hawke@utsouthwestern.edu
authors.forename: T J
authors.initials: TJ
authors.lastname: Hawke
authors.forename: D G
authors.initials: DG
authors.lastname: Allen
authors.forename: M I
authors.initials: MI
authors.lastname: Lindinger
mesh_terms: D000818:Animals; D002110:Caffeine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009994:Osmolar Concentration; D011343:Procaine / Q000494:pharmacology; D013805:Theobromine / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology*
chemical_list: D002110:Caffeine; D011343:Procaine; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine; D002118:Calcium