Apparent frequency-dependent effect of clonidine on cardiac sympathetic transmission: the role of neuronal uptake.

Decreases in spontaneous atrial period (tachycardia) were measured in atropinized guinea-pig isolated right atria in response to intramural sympathetic nerve stimulation. Electrical field pulses were applied only during the atrial refractory period to avoid arrhythmias. Responses to one to six field pulses delivered in a single refractory period were substantially reduced by clonidine (1-1000 nM), providing no evidence that the blocking action of this drug is frequency-dependent. Stimulus-response lines to one, two or four field pulses delivered as one field pulse per refractory period (1/1) were displaced to the right by clonidine (0.1 microM) such that 8, 16 and 32 field pulses were required to obtain responses equivalent to control. Stimulus-response lines to lower frequencies of field stimulation (one field pulse every 4 or 8 refractory periods) were lower in slope and displaced further by clonidine, whereas lines from stimuli at higher frequencies (2/1 and 4/1) were steeper and less displaced by clonidine. These findings confirmed an "apparent" frequency-dependent blocking action of clonidine. However, substantial blockade of neuronal uptake by desipramine (0.1 microM) raised the slope and decreased the shift of the stimulus-response lines to the lower frequencies of field stimulation compared with 2/1 or 4/1. Clonidine (0.1 microM) had no effect on the responses to exogenous norepinephrine. We suggest that clonidine reduces the amount of norepinephrine released per field pulse independently of the frequency of stimulation. The decrease in tissue response may appear to be frequency-dependent under some circumstances due to the effects of uptake and removal processes.