Theophylline inhibition of nucleoside transport and its relation to cyclic AMP in skeletal muscle.

Abstract

Using [14C]inosine and [3H]sorbitol, the effect of theophylline on inosine uptake was studied. Theophylline inhibited the intracellular uptake of inosine by isolated, frog skeletal muscle in a dose-dependent way. An inhibitory effect was also observed for the uptake of labelled adenosine, uridine, hypoxanthine, and adenine, but not for ribose. The inhibition was not readily reversible and was noncompetitive in nature. It was not secondary to the contracture of the muscle produced by the drug, because various treatments known to cause contracture had no effect on inosine transport. Also, papaverine (0.3 mM) significantly inhibited inosine transport without affecting the contractile properties of the muscle. Although theophylline is a cyclic AMP phosphodiesterase inhibitor, no relation could be found between inhibition of inosine uptake and cyclic AMP. N8,O2′-Dibutyryl cyclic AMP (1 mM) was ineffective. Though isoproterenol (10 μg/ml) increased the cyclic AMP concentrations in the muscle by 26-fold in the presence of theophylline and 3-fold in the absence of the drug, it did not influence inosine transport. Tracing the label into various intracellular nucleotides after incubation of the muscle with [14C]inosine suggested that theophylline inhibited inosine transport rather than inosine metabolism.