Extracellular sodium and chloride depletion enhances nonexocytotic noradrenaline release induced by energy deficiency in rat heart.

The effect of either extracellular sodium or extracellular chloride reduction on the release of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylglycol (DOPEG) has been studied in the isolated perfused rat heart under conditions of ischaemia and cyanide intoxication. The overflow of noradrenaline and DOPEG was determined by high pressure liquid chromatography. The efflux of DOPEG, the predominant neuronal noradrenaline adrenaline metabolite, served as indicator of the free axoplasmic plasmic amine concentration. A calcium-free perfusion buffer was used to avoid exocytotic noradrenaline release. Sodium and chloride in the perfusion buffer were replaced by lithium and isethionate, respectively. (1) Reduction of extracellular sodium or chloride increased noradrenaline overflow in ischaemia. The release was suppressed by the uptake1 blocker cocaine indicating carrier-mediated outward transport of noradrenaline. (2) In cyanide intoxication sodium or chloride reduction accelerated the onset of DOPEG efflux reflecting increased axoplasmic noradrenaline concentrations. This was accompanied by increased noradrenaline release. The ratio of noradrenaline/DOPEG overflow was increased by reduced sodium or chloride, indicating facilitation of carrier-mediated noradrenaline net outward transport. (3) In the presence of unaltered energy metabolism overflow of both, noradrenaline and DOPEG, was not enhanced by sodium or chloride reduction. The results demonstrate that reduction of extracellular sodium or chloride has two effects on noradrenaline release from the sympathetic neuron with reduced energy supply. First, reduced sodium or chloride induces increased axoplasmic noradrenaline concentrations by interference with vesicular storage function. Second, both interventions enhance carrier-mediated noradrenaline release.