Mechanism of the negative inotropic action of cocaine in rat papillary muscle.

We studied the mechanism of the negative inotropic action of cocaine in isolated rat papillary muscles superfused with Tyrode's solution at 31 degrees C while attached to a force transducer to measure peak tension developed (PTD), maximum velocity of development of tension (Vmax T), and time to peak tension (TPT). The results show that in preparations driven at 1 Hz, 5 and 10 mg/liter cocaine had a significant negative effect only on PTD, while 20 mg/liter (58 microM) significantly depressed all three measured parameters. Similar results were obtained in preparations driven at 0.5 Hz, which developed a greater control active tension than those driven at 1 Hz. In preparations driven at 0.5 Hz, propranolol (1 microM) had no significant effect on the active tension developed nor did it modify the negative inotropic action of cocaine. Both nifedipine (1 microM) and caffeine (1.5 mM), on the other hand, significantly reduced PTD, Vmax T, and TPT. The depressant inotropic action of cocaine was accentuated by nifedipine, but was blocked by caffeine. These observations suggest that the primary site of action of cocaine was at the level of the sarcoplasmic reticulum rather than at the sarcolemma.