Disadvantages of cocaine as a neuronal uptake blocking agent: comparison with desipramine in guinea-pig right atrium.
Cocaine and desipramine (DMI) are widely used as neuronal uptake blocking agents in studies of cardiac sympathetic transmission in isolated tissue preparations. It is generally assumed that these pharmacological tools do not alter transmitter release or postjunctional effector response. To test this assumption, we have compared the effects of cocaine and DMI on rate responses to sympathetic nerve stimulation and exogenous noradrenaline in guinea-pig isolated right atria. Right atria were equilibrated with the irreversible alpha-adrenoreceptor antagonist benextramine to prevent any effect of presynaptic alpha-adrenoreceptors. Cumulative (-) noradrenaline concentration-response curves were shifted to the left by DMI (0.01-1 microM) without significant change in the resting or maximum rates. Cocaine (1-100 microM) also caused sensitisation to noradrenaline but caused a biphasic change in resting atrial rate. In addition there was a small but significant depression of the maximum rate at cocaine 10 and 100 microM. Sympathetic nerve stimulation was achieved by applying trains of 1, 2 and 4 electrical field pulses delivered during one atrial refractory period. DMI caused a concentration dependent potentiation of responses to field stimulation. Cocaine (1 microM) caused significant enhancement of peak responses to field stimulation but no further enhancement and indeed depressed peak responses were observed at cocaine 10 and 100 microM respectively. The time for atrial period to return halfway to baseline after field stimulation (t 1/2) was enhanced by cocaine in a concentration dependent manner as was observed with DMI. We conclude that cocaine (but not DMI) decreases the maximum response to exogenous noradrenaline (postjunctional depression). The reduction of the peak response to sympathetic nerve stimulation in the presence of cocaine to below control responses suggests that cocaine also depresses the release of transmitter. These additional depressant properties of cocaine, which occur in a concentration range of neuronal uptake block, are important disadvantages and should discourage its use in experiments on sympathetic transmission.
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology
D003042:Cocaine; D007545:Isoproterenol; D003891:Desipramine; D009638:Norepinephrine