TOLBUTAMIDE, BUT NOT GLYBURIDE, AFFECTS THE EXCITABILITY AND CONTRACTILITY OF UNFATIGUED FROG SARTORIUS MUSCLE

The goal of this study was to characterize the effects of tolbutamide and glyburide, two known K(ATP) channel blockers, on intact, unfatigue d sartorius muscle fibres of the frog, Rana pipiens. Tetanic contracti ons were elicited by field stimulation with 200 ms long train of pulse s (0.5 ms, 6 V, 140 Hz). Resting and action potentials were measured u sing conventional microelectrodes. At pH(o) 7.2 (extracellular pH), th e tetanic force was unaffected by 0.5 mM and 1.0 mM tolbutamide, but a t 2.0 mM it decreased by 15.5 +/- 1.0%. The effect of tolbutamide on t he tetanic force was significantly greater at pH. 6.4: all three tolbu tamide concentrations caused a significant decrease in tetanic force, being 62.3 +/- 9.4% at 2. mM. In the presence of tolbutamide a large n umber of fibres became unexcitable at pH(o) 6.4, but not at pH(o) 7.2. Glyburide at 10 muM, on the other hand, caused a 5-7% decrease in tet anic force at both pH(o) 6.4 and 7.2, but no further decreases in teta nic force were observed when the glyburide concentration was increased up to 100 muM. Unlike tolbutamide, glyburide did not affect the excit ability of muscle fibres, but significantly prolonged the repolarizati on phase of action potentials, especially at pH(o) 6.4. We suggest tha t several of the tolbutamide effects reported in this study cannot be accounted for by a direct effect on K(ATP) channels, and that the larg e decrease in membrane excitability and muscle contractility in the pr esence 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.