title: Rapid transcapillary exchange and unidirectional neuronal uptake of noradrenaline in the perfused rabbit heart.
abstract: Capillary permeability and cellular uptake of noradrenaline by the isolated artificially perfused rabbit heart was measured using rapid (less than 30 s) single-circulation tracer-dilution techniques. In a single coronary circulation capillary extractions of L-[14C]noradrenaline and D-[3H]mannitol (extracellular reference) relative to an intravascular marker, 125I-labelled albumin, were similar and above 60%. The 'apparent' volume of distribution for tracer noradrenaline was 2.5-fold larger than that measured for D-mannitol (0.32 ml g-1) suggesting cellular uptake of the amine. Unidirectional noradrenaline uptake was estimated by directly comparing coronary sinus dilution profiles of L-[3H]noradrenaline and D-[14C]mannitol. Michaelis-Menten saturation kinetics based on a single-entry system were determined (Km = 2.8 +/- 1.5 microM, Vmax = 2.1 +/- 0.5 nmol min-1 g-1, n = 4) by perfusing hearts with varying concentrations of L-noradrenaline (1-10 microM). Various known inhibitors of noradrenaline uptake were investigated to determine whether uptake was mediated by neuronal (uptake1) and/or extraneuronal (uptake2) mechanisms. Desipramine (5 microM), imipramine (5 microM) and metaraminol (2 microM) resulted in a 66-94% inhibition of noradrenaline influx. In comparison, the steroids, 17 beta-oestradiol (1 microM) and corticosterone (10 microM), and the noradrenaline metabolite normetanephrine (5 microM) caused virtually no inhibitory effects. The beta-adrenergic antagonist propranolol (5 microM) was also relatively ineffective. These results together with the kinetic constants estimated suggest that the rapid noradrenaline uptake reflects transport into adrenergic neurones lying in the coronary interstitium. The high resolution of this paired-tracer dilution technique has permitted a 'non-invasive' study of neuronal uptake mechanisms and its application may be of clinical value.
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002199:Capillary Permeability; D003345:Corticosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008353:Mannitol / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000929:Antidepressive Agents, Tricyclic; D008353:Mannitol; D004958:Estradiol; D011433:Propranolol; D003345:Corticosterone; D009638:Norepinephrine