The kinetics underlying the uptake of tracer amounts of norepinephrine and isoproterenol by the heart were studied in a pentobarbital-anesthetized dog with the multiple indicator dilution technique. The circumflex coronary artery was perfused with blood from the femoral artery, with a pressure-dependent system. A small bolus containing labeled albumin (a tracer confined to the vascular space), labeled sucrose (which penetrates into the extracellular space in a barrier-limited fashion), and labeled norepinephrine or isoproterenol was injected into the artery and outflow dilution curves were obtained from the coronary sinus. Analysis of data enabled us to assess separately the myocardial capillary permeability for norepinephrine or isoproterenol, and their rate constants for uptake by the interstitial sympathetic fibers (the process is essentially unidirectional over the time of a single passage, because of the highly concentrative nature of the uptake). We found a major resistance to catecholamine transfer at the capillary surface (approximately half of the label emerged at the outflow without leaving the circulation) and a neuronal uptake process beyond the barrier large enough that, after steady infusion, it would be expected to reduce the tracer concentration of norepinephrine to a value the order of one-sixth that in the plasma space. The injection of desmethylimipramine selectively diminished the apparently unidirectional flux of labeled norepinephrine into the neuronal terminals, and this uptake was found to be significantly lower for isoproterenol than for norepinephrine. The capillary-intersti-tium-concentrative uptake mechanism, documented here, partially explains the quantitatively different cardiac responses to infused and locally released catecholamines.Circ Res 47: 329-338, 1980