Phenol is a neurolytic agent used for management of spasticity in patients with either motoneuron lesions or stroke. In addition, compounds that enhance muscle contractility (i.e., polyphenols, etc.) may affect muscle function through the phenol group. However, the effects of phenol on muscle function are unknown, and it was, therefore, the purpose of the present investigation to examine the effects of phenol on tension development and Ca(2+) release in intact skeletal muscle fibers. Dissected intact muscle fibers from Xenopus laevis were electrically stimulated, and cytosolic Ca(2+) concentration ([Ca(2+)](c)) and tension development were recorded. During single twitches and unfused tetani, phenol significantly increased [Ca(2+)](c) and tension without affecting myofilament Ca(2+) sensitivity. To investigate the phenol effects on Ca(2+) channel/ryanodine receptors, single fibers were treated with different concentrations of caffeine in the presence and absence of phenol. Low concentrations of phenol significantly increased the caffeine sensitivity (P < 0.01) and reduced the caffeine concentrations necessary to produce nonstimulated contraction (contracture). However, at high phenol concentrations, caffeine did not increase tension or Ca(2+) release. These results suggest that phenol affects the ability of caffeine to release Ca(2+) through an effect on the ryanodine receptors, or on the sarcoplasmic reticulum Ca(2+) pump. During tetanic contractions inducing fatigue, phenol application decreased the time to fatigue. In summary, phenol increases intracellular [Ca(2+)] during twitch contractions in muscle fibers without altering myofilament Ca(2+) sensitivity and may be used as a new agent to study skeletal muscle Ca(2+) handling.