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 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)
D000818:Animals; D005711:Gallopamil / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013564:Sympathetic Nervous System / Q000378:metabolism; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology*
D005711:Gallopamil; D014700:Verapamil; D009638:Norepinephrine