MECHANISM OF THEOPHYLLINE-INDUCED INOTROPIC EFFECTS ON FORESHORTENED CANINE DIAPHRAGM

The mechanisms of theophylline-induced inotropic effects at shorter di aphragm length have not yet been explored, We wondered whether the gre ater inotropic effects of the drug at shorter diaphragm length might r esult from an effect on intracellular calcium level, Forty pairs of di aphragm bundles were stimulated at 70% of optimal length in the presen ce of either verapamil (10(-5) M), calcium-free Krebs solution (buffer ed or not with 2 mM ethylene glycol tetra-acetic acid (EGTA)) or ryano dine (10(-6) M), Theophylline (1 mM) was subsequently added to one mus cle bundle and, after 15 min, twitches were repeated, The twitch poten tiation induced by theophylline (37+/-21%) was unaffected by verapamil (43+/-26%), or zero calcium (39+/-18%) and virtually unchanged when t he latter was buffered with EGTA. By contrast, theophylline failed to increase twitch tension after pretreatment with ryanodine, a blocker o f the calcium release by the sarcoplasmic reticulum. This decreased tw itch tension in control (-5+/-11%) and experimental (-14+/-12%) bundle s and prolonged half-relaxation time as a result of impaired sarcoplas mic reticulum calcium reuptake. We conclude that the inotropic effects of theophylline on twitch tension in foreshortened canine diaphragm b undles were not related to transmembrane calcium flux but were depende nt on the release of calcium from the sarcoplasmic reticulum, This is consistent with an action of theophylline on the sarcoplasmic reticulu m.