Diltiazem, verapamil, and nifedipine inhibit theophylline-enhanced diaphragmatic contractility

The ability of theophylline to limit diaphragmatic fatigue and to improve contractility appears to be dependent upon alterations in calcium metabolism. The mechanism responsible for these actions, however, remains unclear. We used perfused, contracting, intact rat diaphragm to measure the influence of therapeutic theophylline levels (10(-4) M) on tension development, in the presence or absence of the three most commonly used calcium channel blocking agents, or in the absence of calcium. Concentrations of diltiazem (10(-4) M), verapamil (10(-5) M), or nifedipine (10(-6) M) sufficient to completely block transmembrane calcium channels, were used. During the experiment, each diaphragm preparation was subjected to one of two fatiguing procedures: one to mimic that encountered during tachypnea and one to mimic that encountered during increased respiratory resistance. Our findings showed that therapeutic levels of theophylline were related to statistically significant (p less than 0.0005) increases in diaphragmatic contractility under control conditions and to statistically significant reductions in the sensitivity of the preparation to fatigue. All three calcium channel blockers negated the positive influence of theophylline. Zero calcium also prevented theophylline from enhancing the contractile properties of the diaphragm. It is our conclusion that theophylline enhances the contractile properties of the diaphragm by altering the transmembrane movement of calcium. Calcium antagonists, in turn, inhibit the beneficial effects of theophylline on diaphragm function.