Key result
A single 5-mg/kg dose of D-600 caused a significant depletion of noradrenaline content in rat ventricles by approximately 31%, an effect that was reversible and likely due to direct intraneuronal action.
The calcium-channel blocker D-600 depletes cardiac noradrenaline stores, likely through a direct action on sympathetic nerves causing intraneuronal release.
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Indicates potential off-target sympathetic effects in preclinical calcium-channel blocker studies; leaves open clinical relevance in humans.
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 chromatograph 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 of 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 greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
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Chaudhry et al. (1984) studied this question. D-600 was evaluated on Depletion of noradrenaline content of the ventricles. A single 5-mg/kg dose of D-600 caused a significant depletion of noradrenaline content in rat ventricles by approximately 31%, an effect that was reversible and likely due to direct intraneuronal action.
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