THE RELEASE OF GUANETHIDINE AND BETHANIDINE BY SPLENIC NERVE STIMULATION: A QUANTITATIVE EVALUATION SHOWING DISSOCIATION FROM ADRENERGIC BLOCKADE

¹ Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee

The question of whether guanethidine and bethanidine block adrenergic nerve transmission by acting as false neurotransmitter substances has been investigated using the isolated perfused cat spleen. Spleens were labeled with ³H-guanethidine or ¹⁴C-bethanidine by a 20-minute exposure and recovery then followed for two to three hours during perfusion with drug-free perfusate. After just maximal blocking doses, splenic nerve stimulation released neither norepinephrine nor guanethidine or bethanidine. During recovery, progressively more norepinephrine was released during nerve stimulation, and the output of guanethidine and bethanidine was directly proportional to the amount of true transmitter released. During this time adrenergic blockade was related to the concentration of the guanidiniums in the effluent perfusate without stimulation. When phenoxybenzamine was added to the perfusate after administration of the guanidiniums, proportionately more norepinephrine was released than guanethidine or bethanidine, but a straight line relationship between the output of norepinephrine and the guanidiniums was still apparent. Pretreatment with phenoxybenzamine prevented the uptake of the guanidiniums by the spleen and, as a result, they were not subsequently released on nerve stimulation. These experiments show that the adrenergic neuron block produced by acute exposure to guanethidine and bethanidine does not result from their replacement of norepinephrine as false transmitters, and that the presence of these drugs within the synaptic vesicles does not contribute substantially to their effects. However, such an effect during chronic drug administration has not been excluded.