SODIUM-DEPENDENT SECRETION AND RETENTION OF NE IN ADRENERGIC TERMINALS

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Mechanisms for both Na+-dependent hypertension and the therapeutic effect of Li+ are not known. This report supports the hypothesis that Na regulates the secretion and recapture of NE from a pool of mobile amine in adrenergic terminals in rat heart slices. Lithium produces a functional deficiency of Na. Mobilized NE was accumulated in terminals as a result of metabolic deficiencies during the overnight dialysis of terminals in solutions of either Na, K, Li or choline at 0 degrees. The axolemma was the dialysis membrane. The mobilized NE was depleted during a subsequent incubation of terminals in Krebs medium (KRB) at 37 degrees. The rapidly induced depletion was independent of the primary dialysis cation, and, the presence of Ca in the KRB. Depletion was inhibited by either dialyzed (intraterminal) ATP or import export blockers such as cocaine. These agents in the incubation medium were not inhibitory. The depletion of mobile NE differed from the secretion of vesicular NE. Forty percent of the remaining NE was stably retained in synaptic vesicles. Secretion from vesicles was evoked by the incubation of terminals in a Na-deprived (Choline) KRB (Ch-Ca). Secretion was delayed, dependent upon intraterminal Na, and, Ca in the medium. Secretion was mediated by export from a previously described vesicular-axolemmal secretory and transmitter recovery unit comprised of vesicles whose membranes had fused with the axolemma. Bound intravesicular NE was mobilized in the process then exported. The vesicle membrane was accessible to ATP in the medium. In non-dialyzed terminals, secretion was inhibited by ATP only when Na was present. Thus, Na was required for the translocation of NE into and out of terminals. Lithium, in a therapeutic concentration of I mM prevented the vesicle from recapturing released or mobilized NE. This effect was indicated by an increased deamination of NE. Thus, Li appeared to interfere with a requirement for Na in the recapture process in an active unit. On the basis of published reports, Li may act by inhibiting Mg-ATPase activity and dependent NE uptake in isolated synaptic vesicles. The present report adds the important information that Li can act in therapeutic concentrations on vesicles in situ. Since Li stimulates deamination in rat brain in vivo, the postulated role for Na may be relevant therapeutically.