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Effects of diltiazem (3 micrograms-0.3 mg), verapamil (3 micrograms-0.3 mg), tetracaine (30 micrograms-3 mg), MnCl2 (0.1 mg-10 mg) and CaCl2 (0.1 mg-10 mg) on the skeletal muscle contracture induced by KCl and caffeine infusions were studied in the isolated, blood-perfused canine diaphragm preparation. All drugs were injected intra-arterially. Continuous intra-arterial infusion of KCl (50-100 mg/min) produced a biphasic contracture, which was characterized by a fast phasic contracture and a following tonic contracture. All drugs tested in this study except for CaCl2 produced a dose-dependent relaxation in the state of tonic contracture induced by KCl infusion. Dose-response curves for the relaxation of muscle to these drugs were all in parallel. Diltiazem and verapamil were equipotent and were about 10 and 30 times more potent than tetracaine and MnCl2 on a weight basis. Conversely, CaCl2 produced a contractile response in a dose-dependent manner. On the other hand, diltiazem, verapamil and CaCl2 had almost no effect on contracture induced by continuous intra-arterial infusion of caffeine (20 mg/min). MnCl2 produced a slight relaxation in the caffeine-contracture with much higher doses than those against potassium-contracture. However, tetracaine produced a dose-dependent relaxation of caffeine-contracture. Thus, the results suggest that the entry of external calcium plays an essential role in the potassium-induced tonic contracture and that the potassium- and caffeine-contractures were maintained by different mechanisms.

Mechanisms of slow contracture induced by potassium and caffeine in skeletal muscle of the dog.