Tolbutamide, but not glyburide, affects the excitability and contractility of unfatigued frog sartorius muscle

Abstract

The goal of this study was to characterize the effects of tolbutamide and glyburide, two known K ATP channel blockers, on intact, unfatigued sartorius muscle fibres of the frog, Rana pipiens. Tetanic contractions were elicited by field stimulation with 200 ms long train of pulses (0.5 ms, 6 V, 140 Hz). Resting and action potentials were measured using conventional microelectrodes. At pH o 7.2(extracellular pH), the tetanic force was unaffected by 0.5 mM and 1.0 mM tolbutamide, but at 2.0 mM it decreased by 15.5±1.0%. The effect of tolbutamide on the tetanic force was significantly greater at pH o 6.4: all three tolbutamide concentrations caused a significant decrease in tetanic force, being 62.3±9.4% at 2 mM. In the presence of tolbutamide a large number of fibres became unexcitable at pH o 6.4, but not at pH o 7.2. Glyburide at 10 μM, on the other hand, caused a 5–7% decrease in tetanic force at both pH o 6.4 and 7.2, but no further decreases in tetanic force were observed when the glyburide concentration was increased up to 100 μM. Unlike tolbutamide, glyburide did not affect the excitability of muscle fibres, but significantly prolonged the repolarization phase of action potentials, especially at pH o 6.4. We suggest that several of the tolbutamide effects reported in this study cannot be accounted for by a direct effect on K ATP channels, and that the large decrease in membrane excitability and muscle contractility in the presence of tolbutamide must seriously be taken into consideration when this channel blocker is used to study the physiological role of K ATP channels in intact muscle fibres.