Na(+)-Ca2+ exchange activity in central nerve endings. II. Relationship between pharmacological blockade by amiloride analogues and dopamine release from tuberoinfundibular hypothalamic neurons

M Taglialatela, LM Canzoniero, EJ Cragoe , G Di Renzo and L Annunziato

Institute of Pharmacology, 2nd School of Medicine, University of Naples, Italy.

The aim of the present study was to investigate the possible role played by the Na(+)-Ca2+ exchange system in the modulation of [3H]dopamine ([3H]DA) release from tuberoinfundibular hypothalamic (TIDA) neurons. 2',4'-Dimethylbenzamil (DMB) dose-dependently (10-100 microM) inhibited Na(+)-dependent 45Ca2+ efflux from brain synaptosomes. This compound (30-300 microM), as well as alpha- phenylbenzamil amiloride (30-100 microM), another inhibitor of the Na(+)-Ca2+ antiporter, was also able to stimulate basal release of [3H]DA from superfused TIDA neurons. This stimulation was completely prevented by the removal of extracellular Ca2+ ions, in the presence of 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In addition, DMB-induced [3H]DA release was unaffected by the dopamine transport inhibitor nomifensine (10 microM). On the other hand, 5-[N-methyl-N-guanidinocarbonylmethyl]amiloride (MGCMA) (100-300 microM), which lacks inhibitory properties on the Na(+)-Ca2+ exchanger but behaves as an inhibitor of the Na(+)-H+ antiporter, failed to modify basal [3H]DA release from TIDA neurons. When the Na(+)-Ca2+ antiporter operates as a Ca2+ influx pathway, as occurs upon the removal of extracellular Na+ ions, Na(+)-dependent 45Ca2+ uptake in brain synaptosomes was dose-dependently (10-300 microM) inhibited by DMB, whereas DMB itself was unable to prevent 55 mM K(+)-induced 45Ca2+ uptake, which mainly reflects the activation of voltage-operated Ca2+ channels. In keeping with these results, ouabain (500 microM)-induced [3H]DA release, which depends on the activation of the Na(+)-Ca2+ exchanger due to inhibition of the Na(+)-K(+)-ATPase pump, was prevented by superfusion of TIDA neurons with DMB (50 microM). By contrast, MGCMA (100 microM) failed to modify either Na(+)-dependent 45Ca2+ influx or ouabain-induced [3H]DA release. In conclusion, the results of the present study appear to suggest that the pharmacological inhibition of the Na(+)-Ca2+ antiporter by amiloride analogues may affect DA release from central neurons. Opposite effects are observed, depending on the direction of operation of the exchanger. In fact, when the Na(+)-Ca2+ exchanger operates as a Ca2+ efflux pathway, its pharmacological blockade can produce a stimulation of DA release. In contrast, when this antiporter operates as a Ca2+ influx pathway, as occurs as a consequence of the inhibition of the Na(+)-K(+)-ATPase pump by ouabain, its pharmacological blockade can prevent ouabain-induced DA release from TIDA neurons.

Volume 38, Issue 3, pp. 393-400, 09/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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