The effects of cocaine on spontaneous pre- and postganglionic sympathetic nerve activity (SNA), mean blood pressure and heart rate were assessed in anesthetized cats. I.v. administration of 2 and 4 mg/kg decreased preganglionic SNA by -24 +/- 7% (n = 4) and -63 +/- 15% (n = 5), respectively. The 4 mg/kg dose produced a decrease in mean blood pressure (-49 +/- 6 mm Hg) with no change in heart rate. Similar sympathoinhibition was obtained in animals with denervated cardiovascular reflexes. Cocaine methiodide (4 mg/kg), a quaternary derivative of cocaine with limited central nervous system access, reduced mean blood pressure (-47 +/- 9 mm Hg) but did not inhibit preganglionic SNA. Cocaine (4 mg/kg) also reduced sympathetic discharge to the adrenal medulla as evidenced by a -62 +/- 6% (n = 5) decrease in splanchnic nerve firing. Cocaine, 2 and 4 mg/kg i.v., decreased postganglionic cardiac SNA by -54 +/- 5% (n = 7) and -60 +/- 13% (n = 4), respectively. The 2 mg/kg dose depressed postganglionic SNA to a greater extent that it did preganglionic SNA. Furthermore, cocaine methiodide (2 mg/kg) reduced postganglionic SNA by -85 +/- 15%. The depressant effect of cocaine (2 mg/kg) on postganglionic cardiac SNA was attenuated after treatment with phentolamine (5 mg/kg i.v.). Lidocaine administered in doses equimolar to those of cocaine did not significantly affect sympathetic discharge. These results indicate that cocaine acts in the central nervous system and at the stellate ganglion to inhibit sympathetic discharge and that these sympathoinhibitory effects are unrelated to cocaine's local anesthetic action.