Summary
The fate of adrenaline released from cardiac sympathetic nerves was compared with that of noradrenaline before and during two periods of electrical stimulation of the left ansa subclavia in eight anaesthetized dogs. Cardiac spillovers and extractions of both catecholamines were estimated simultaneously using infusions of 3H-labelled adrenaline and noradrenaline. Animals were studied before and after neuronal uptake blockade with desipramine.
Cardiac spillover of adrenaline, detectable at rest at 1.4 ± 0.3 pmol/min, increased to 4.0 ± 1.1 and 5.3 ± 1.2 pmol/min during sympathetic stimulation. Cardiac noradrenaline spillover increased from 49 ± 12 to 205 ± 40 and 451 ± 118 pmol/min. After desipramine, cardiac spillovers of adrenaline were decreased, whereas those of noradrenaline were increased so that the ratio of adrenaline to noradrenaline spillover, meaned before and during stimulation, decreased substantially from 1:42 to 1:166. The desipramine-induced decrease in cardiac extractions of 3H-labelled catecholamines indicated adrenaline was removed 60% less efficiently than noradrenaline by neuronal uptake, whereas the extractions remaining indicated adrenaline was removed 50% more efficiently by extraneuronal uptake.
The differences in removal processes indicated that 35% of the adrenaline released by cardiac sympathetic nerves was recaptured compared to 88% for noradrenaline, leaving 53% to be removed extra-neuronally compared to 6.6% for noradrenaline, so that proportionally more released adrenaline than noradrenaline escaped to spillover into plasma (12% versus 5.4%). Since extraneuronal uptake was more efficient for adrenaline than noradrenaline, proportionally less released adrenaline than noradrenaline escaped local removal to spillover into plasma when neuronal uptake was blocked (17% versus 45%). This reversed the situation before blockade so that desipramine substantially decreased the ratio of adrenaline to noradrenaline spillover. Thus, differences in the efficiencies of neuronal or extraneuronal uptake are important determinants of the amounts of locally released adrenaline and noradrenaline that escape removal processes to act at neuroeffector sites or spillover into plasma.
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References
Andén N-E (1964) Uptake and release of dextro- and laevo-adrenaline in noradrenergic stores. Acta Pharmacol Toxicol 21:59–75
Axelrod J (1960) The fate of adrenaline and noradrenaline. In: Vane JR, Wolstenholme GEW, O'Connor M (eds) Adrenergic mechanisms. Boston, Little, Brown & Co, pp 28–39
Belfrage E, Fredholm BB, Rosell S (1977) Effect of catechol-O-methyl-transferase (COMT) inhibition on the vascular and metabolic response to noradrenaline, isoprenaline and sympathetic nerve stimulation in canine subcutaneous adipose tissue. Naunyn Schmiedeberg's Arch Pharmacol 300:11–17
Brock JA, Cunnane TC, Starke K, Wardell CF (1990) α2-Adrenoceptor-mediated autoinhibition of sympathetic transmitter release in guinea pig vas deferens studied by intracellular and focal extracellular recording of junction potentials and currents. Naunyn-Schmiedeberg's Arch Pharmacol 342:43–52
Brown MJ, Macquin I (1981) Is adrenaline the cause of essential hypertension? Lancet 2:1079–1082
Carty SE, Johnson RG, Vaughan T, Pallant A, Scarpa A (1985) Amine transport into chromaffin ghosts. Kinetic measurements of net uptake of biologically and pharmacologically relevant amines using an on-line amperometric technique. Eur J Biochem 147:447–452
Chang PC, Szemeredi K, Grossman E, Kopin IJ, Goldstein DS (1990) Fate of tritiated 6-fluorodopamine in rats: A false neurotransmitter for positron emission tomographic imaging of sympathetic innervation and function. J Pharmacol Exp Ther 255:809–817
Cohen MD, Finberg J, Dibner-Dunlap M, Yuih SN, Thames MD (1990) Effects of desipramine hydrochloride on peripheral sympathetic nerve activity. Am J Physiol 258:R876-R882
Cousineau D, Goresky CA, Rose CP (1986) Decreased basal cardiac interstitial norepinephrine release after neuronal uptake inhibition in dogs. Circ Res 58:859–866
Dunnett CW (1964) New tables for multiple comparisons with a control. Biometrics 20:482–491
Eisenhofer G, Goldstein DS, Kopin IJ (1989) Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal re-uptake in the sympathetic nervous system in vivo. Clin Sci 76:171–182
Eisenhofer G, Esler MD, Cox HS, Meredith IT, Jennings GL, Brush JE, Goldstein DS (1990) Differences in the neuronal removal of circulating epinephrine and norepinephrine. J Clin Endocrinol Metab 70:1710–1720
Eisenhofer G, Smolich J, Cox HS, Ester MD (1991) Neuronal reuptake of norepinephrine and production of dihydroxyphenylglycol by cardiac sympathetic nerves in the anesthetized dog. Circulation 84:1354–1363
Elayan HH, Kennedy BP, Ziegler MG (1990) Cardiac atria and ventricles contain different inducible adrenaline synthesizing enzymes. Cardiovasc Res 24:53–56
Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P (1984) Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol 247:E21-E28
Esler M, Eisenhofer G, Chin J, Jennings G, Meredith I, Cox H, Lambert G, Thompson J, Dart A (1991a) Is adrenaline released by sympathetic nerves in man? Clin Auton Res 1:103–108
Esler M, Wallin G, Dorward P, Eisenhofer G, Westerman R, Meridith I, Lambert G, Cox H, Jennings G (1991b) Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in man. Am J Physiol 260:R817-R823
Friberg P, Meredith I, Jennings G, Lambert G, Fazio V, Esler M (1990) Evidence for increased renal norepinephrine overflow during sodium restriction in humans. Hypertension 16:121–130
Goldstein DS, Zimlichman R, Stull R, Keiser HR, Kopin IJ (1986) Estimation of intrasynaptic norepinephrine concentrations in humans. Hypertension 8:471–475
Graefe K-H (1981) The disposition of 3H-(−)noradrenaline in the perfused cat and rabbit heart. Naunyn-Schmiedeberg's Arch Pharmacol 318:71–82
Graefe K-H, Bönisch H (1988) The transport of amines across the axonal membranes of noradrenergic and dopaminergic neurones. In: Trendelenburg U, Weiner N (eds) Catecholamines I. Springer, New York Berlin Heidelberg, pp 193–245
Graefe K-H, Henseling M (1983) Neuronal and extraneuronal uptake and metabolism of Catecholamines. Gen Pharmacol 14:27–33
Grohmann M, Trendelenburg U (1984) The substrate specificity of uptake2 in the rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 328:164–173
Halbrügge T, Wölfel R, Graefe K-H (1989) Plasma 3,4-dihydroxyphenylglycol as a tool to assess the role of neuronal uptake in the anaesthetized rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 340:726–732
Iversen LL (1963) The uptake of noradrenaline by the isolated perfused rat heart. Br J Pharmacol 21:523–537
Iversen LL (1965a) The uptake of adrenaline by the rat isolated heart. Br J Pharmacol 24:387–394
Iversen LL (1965b) The uptake of Catecholamines at high perfusion concentrations in the rat isolated heart: a novel catecholamine uptake process. Br J Pharmacol 25:18–33
Iwamoto HS, Rudolph AM (1983) Chronic venous catherization in fetal sheep. Am J Physiol 245:H524-H527
Kopin IJ, Hertting G, Gordon EK (1962) Fate of norepinephrine-H3 in the isolated perfused rat heart. J Pharmacol Exp Ther 138:34–40
Kopin IJ, Zukowska-Grojec Z, Bayorh MA, Goldstein DS (1984) Estimation of intrasynaptic norepinephrine concentrations at vascular neuroeffector junctions in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 325:298–305
Ludwig J, Gerlich M, Halbrügge T, Graefe K-H (1990) The synaptic noradrenaline concentration in humans as estimated from simultaneous measurements of plasma noradrenaline and dihydroxyphenylglycol. J Neural Transm 32:441–445
Majewski H, McCulloch MW, Rand MJ, Story DF (1980) Adrenaline activation of prejunctional \-adrenoceptors in guinea-pig atria. Br J Pharmacol 71:435–444
Masuda Y, Levy MN (1984) The effects of neuronal uptake blockade on the cardiac responses to sympathetic nerve stimulation and norepinephrine infusion in anesthetized dogs. J Auton Ner Syst 10:1–17
Medvedev OS, Esler M, Angus JA, Cox HS, Eisenhofer G (1990) Simultaneous determination of plasma noradrenaline and adrenaline kinetics: Responses to nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 341:192–199
Paiva MQ, Guimaraes S (1978) A comparative study of the uptake and metabolism of noradrenaline and adrenaline by the isolated saphenous vein of the dog. Naunyn-Schmiedeberg's Arch Pharmacol 303:221–228
Peronnet F, Nadeau R, Boudreau G, Cardinal R, Lamontagne D, Yamaguchi N, De Champlain J (1988) Epinephrine release from the heart during left stellate ganglion stimulation in dogs. Am J Physiol 254:R659-R662
Rand MJ, Majewski H (1984) Adrenaline mediates a positive feedback loop in noradrenergic transmission: its possible role in development of hypertension: Clin Exp Hypertens Part A Theory Pract 1 and 2:347–370
Rosell S, Axelrod J, Kopin IJ (1964) Release of tritiated epinephrine following sympathetic nerve stimulation Nature (Lond) 201: 301
Schömig E, Fischer P, Schönfeld C-L, Trendelenburg U (1989) The extent of neuronal reuptake of 3H-noradrenaline in isolated vasa deferentia and atria of the rat. Naunyn-Schmiedeberg's Arch Pharmacol 340:502–508
Szabo B, Schultheiss A (1990) Desipramine inhibits sympathetic nerve activity in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 342:469–476
Trendelenburg U (1986) The metabolizing system involved in the inactivation of catecholamines. Naunyn-Schmiedeberg's Arch Pharmacol 332:201–207
Trendelenburg U (1988) The extraneuronal uptake and metabolism of catecholamines. In: Trendelenburg U, Weiner N (eds) Cat echolamines I. Springer, Berlin Heidelberg New York, pp 279–319
Trendelenburg U, Schönfeld C-L, Schömig E (1990) The efficiency of the neuronal re-uptake of noradrenaline — and the inhomogeneity of labelling of an incubated tissue. Neurochem Int 17:139–147
Yamaguchi N, de Champlain J, Nadeau RA (1977) Regulation of norepinephrine release from cardiac sympathetic fibers in the dog by presynaptic α- and \-receptors. Circ Res 41:108–117
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Eisenhofer, G., Smolich, J.J. & Ester, M.D. Disposition of endogenous adrenaline compared to noradrenaline released by cardiac sympathetic nerves in the anaesthetized dog. Naunyn-Schmiedeberg's Arch Pharmacol 345, 160–171 (1992). https://doi.org/10.1007/BF00165731
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DOI: https://doi.org/10.1007/BF00165731