Specific binding of reserpine—: Association with norepinephrine depletion

Abstract

Small doses of 3H-reserpine (10–100 μg/kg) were injected i.v. into rats and the drug concentration in heart, spleen and liver measured at various intervals. Eighteen hours after a dose of 25 μg per kg, concentrations of the tritiated compound were: 4.98 ng per g heart, 6.39 ng per g spleen, and 1.48 ng per g liver. The biologic half-life of 3H-reserpine in heart and spleen was about 18 hr; that of liver was about 4 hr. Specificity studies showed that the labeled material extracted from rat heart 18 hr after administration of the tritiated compound behaved similarly to authentic reserpine. Pretreatment of rats with tetrabenazine (20 mg/kg) or unlabeled reserpine (0.5 mg/kg) significantly reduced the amount of 3H-reserpine found in heart and spleen 18 hr after administration of the radioactive drug, while administration of either tetrabenazine or unlabeled reserpine after the injection of 3H-reserpine had no significant effect on levels of the labeled drug. The concentration of norepinephrine remaining in heart 18 hr after the administration of small doses of reserpine was inversely related to the concentration of persisting drug and the correlation was highly significant. It is concluded that the persistent depletion of norepinephrine by small doses of reserpine is induced and maintained by the physical presence of minute amounts of very highly bound reserpine. Calculations reveal that each molecule of reserpine persisting in heart is associated with a deficit of about 500 norepinephrine molecules. It is also calculated that about 20 molecules of reserpine persist for each affected catecholamine-containing granule.