NONEXOCYTOTIC NORADRENALINE RELEASE FROM RAT CARDIAC SYNAPTOSOMAL-MITOCHONDRIAL FRACTIONS

Nonexocytotic noradrenaline (NA) release was examined in rat cardiac s ynaptosomal-mitochondrial fractions prelabeled with [H-3]NA (300 nM; 1 h at 37 degrees C). Ischemic conditions (1 mM iodoacetate + 2 mM NaCN ; 15 min at 37 degrees C) evoked a Ca2+-independent release of [H-3]NA from isolated synaptosomes, which represented 33.4% of total content, whereas the release evoked by 56 mM K+ was Ca2+ dependent and represe nted 5.8% of total content. Tyramine, phencyclidine (PCP), and rimcazo le also caused important Ca2+-independent releases of [H-3]NA (from 12 to 45% of total content) with median effective concentrations (EC(50) s) of 6.8, 182, and 41.8 mu M, respectively. The release responses evo ked by ischemic conditions, tyramine, PCP, and rimcazole were mimicked by the sigma-receptor ligand, 1,3-ditolyl guanidine (DTG), and blocke d by the uptake(1) inhibitor, desipramine (100 mu M). The sigma(1)-rec eptors ligands, (+)-3-hydroxyphenyl-N-(1-propyl)piperidine ((+)-3-PPP) and (+)N-allylnormetazocine [(+)SKF-10047], were potent blockers of t he release of [H-3]NA evoked by ischemic conditions but not by PCP or rimcazole. These data indicate that ischemic conditions and PCP/sigma( 2)-receptor ligands induce carrier-mediated NA efflux from cardiac sym pathetic nerve terminals, whereas sigma(1)-receptor ligands produce ma rked inhibition of the ischemic response.