Depletion of cardiac noradrenaline stores by the calcium-channel blocker D-600

The actions of the calcium-channel blocker D-600 on cardiac noradrenaline stores were investigated by giving rats the drug systemically and then using a high-performance liquid chromatography equipped with an electrochemical detector to determine the noradrenaline content of their hearts. A single 5-mg/kg dose of D-600 caused a significant depletion of noradrenaline content of the ventricles (approximately 31%) but not the auricles. However, when multiple doses of D-600 were given at 12-h intervals, the depletion of cardiac noradrenaline content was more marked and both the auricular and ventricular contents were significantly decreased. Depletion of noradrenaline content was maximal 4 h after administration of D-600. A partial recovery of noradrenaline content occurred 16 h after administration of D-600, indicating that this effect of D-600 is reversible. In in vitro studies, D-600 (10^-7 to 10^-3 M) evoked a dose-related increase in the basal outflow of tritium from the rat isolated atria preloaded with [³H]noradrenaline ([³H]NA), indicating that depletion of cardiac noradrenaline stores by D-600 may be due to a direct action on sympathetic nerves rather than to increased reflex sympathetic activity, secondary to profound vasodilation caused by the drug. The metabolic profile of tissue ³H content and of D-600 evoked ³H overflow was also examined. Whereas >90% of tissue ³H content consisted of unchanged [³H]NA, 60-70% of the D-600-evoked overflow consisted of [3,4-³H]dihydroxyphenylglycol, and approximately 5% was unchanged NA, thus indicating that D-600 causes release of [³H]NA intraneuronally. It is concluded that this property of D-600 might be responsible for the depletion of endogenous cardiac noradrenaline stores after systemic administration of the drug to rats.