Decreased basal cardiac interstitial norepinephrine release after neuronal uptake inhibition in dogs

The effect of neuronal uptake inhibition on basal interstitial release of norepinephrine in the canine heart was examined by use of the multiple tracer dilution-bulk balance technique. A kinetic model incorporating the effects of flow, capillary permeability-surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate rates of uptake from and release of norepinephrine into the interstitial space. The intravenous injection of the neuronal uptake inhibitor desipramine in anesthetized dogs under basal conditions reduced interstitial uptake of tracer norepinephrine in the heart, without significant changes in plasma concentration of norepinephrine in aorta and coronary sinus. The lack of change in the arteriovenous balance for norepinephrine across the heart, in the face of the lowered uptake for this amine, suggested that the liberation of norepinephrine by cardiac sympathetic fibers was reduced. Analysis of the data with the norepinephrine tracer kinetic-bulk model showed that, after desipramine, the interstitial release of norepinephrine was reduced to the same extent as uptake was diminished. As a result, the concentration of norepinephrine in the extracellular space of the heart did not increase significantly. The findings indicate the presence of a presynaptic neuronal feedback inhibition of release, which serves to fine tune the myocardial interstitial concentration of norepinephrine in the basal state; with this, after desipramine, both norepinephrine uptake and release are correspondingly diminished.