Summary
The removal of noradrenaline by the autoperfused hind-limb of dogs anaesthetized with pentobarbital, as well as the accumulation of noradrenaline in the saphenous vein were studied. Sensitivity of the perfused vascular area was determined by the response of the perfusion pressure to infusions of noradrenaline.
The removal of noradrenaline declined very slowly during infusions lasting for up to 2 h, but edema of the perfused limb occurred after 45 to 60 min; therefore, the duration of infusion was limited to 30 min. During this period, noradrenaline was infused in rates increasing by a factor of 2 and ranging from 0.5 to 16 μg/kg per minute. Accumulation capacity was saturated at 1 μg/kg · min−1, but the amount removed increased until a four-to eightfold rate was reached and then levelled off.
At a rate of 1 μg/kg · min−1 the influence of drugs and of surgical denervation was investigated in other experimental series. Cocaine, nialamide, phenoxybenzamine and pretreatment with reserpine reduced removal (by 50, 45, 40 and 35%, respectively). Cortexone had no detectable influence on removal with this rate of infusion, but blocked it effectively when 4 μg/kg · min−1 were infused. Accumulation of noradrenaline in the vein was prevented by cocaine or reserpine, slightly reduced by phenoxybenzamine and enhanced by nialamide. The effects of nialamide plus cocaine did not differ significantly from those of cocaine alone, but cortexone plus cocaine completely blocked removal and accumulation. Surgical denervation reduced removal by about 70% and abolished accumulation; reserpine plus nialamide had similar effects. In the case of nialamide, removal progressively diminished during the infusion period and this time dependence of effects was accompanied by a prolongation of noradrenaline washout.
Cocaine, reserpine and denervation caused supersensitivity of the perfused vessels to noradrenaline, whereas nialamide and cortexone had no such effect and phenoxybenzamine caused subsensitivity.
The pronounced ability of the perfused vessels of the hind-limb to remove noradrenaline from the circulating blood is attributed primarily to neuronal uptake and intraneuronal oxidative deamination; extraneuronal uptake and inactivation seem to play an important role when neuronal mechanisms are saturated (infusion of higher noradrenaline doses) or impaired (after cocaine or denervation).
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References
Axelrod, J., Cohn, C. K.: Methyltransferase enzyme in red blood cells. J. Pharmacol. exp. Ther. 176, 650–654 (1971)
Berkowitz, B. A., Tarves, J. H., Spector, S.: Norepinephrine in blood vessels: concentration, binding, uptake, and depletion. J. Pharmacol. exp. Ther. 177, 119–126 (1971).
Celander, O., Mellander, S.: Elimination of adrenaline and noradrenaline from the circulating blood. Nature (Lond.) 176, 973–974 (1955).
De La Lande, I. S., Frewen, D., Waterson, J. G.: The influence of sympathetic innervation on vascular sensitivity to noradrenaline. Brit. J. Pharmacol. 31, 82–92 (1967).
Euler, U. S. von, Floding, I.: A fluorimetric micromethod for differential estimation of adrenaline and noradrenaline. Acta physiol. scand. 33, Suppl. 118, 45–62 (1955).
Ginn, R. W., Vane, J. R.: Disappearance of catecholamines from the circulation. Nature (Lond.) 219, 740–742 (1968).
Graefe, K. H., Bönisch, H., Trendelenburg, U.: Time dependent changes in neuronal net uptake of noradrenaline after pretreatment with pargyline and/or reserpine. Naunyn-Schmiedebergs Arch. Pharmak. 271, 1–28 (1971).
Gryglewski, R., Vane, J. R.: The inactivation of noradrenaline and isoprenaline in dogs. Brit. J. Pharmacol. 39, 573–584 (1970).
Guimarães, S., Brandão, F.: The role of monoamine oxidase and catechol-O-methyl transferase in normal and denervated preparations. Fifth Internat. Congr. Pharmacol., Abstr. 543 (1972).
Guimarães, S., Brandão, F.: Comparison between the effects produced by chronic denervation and by cocaine on the sensitivity to, and on the disposition of, noradrenaline in isolated spleen strips. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 163–174 (1973).
Guimarães, S., Osswald, W., Cardoso, W., Branco, D.: The effects of cocaine and denervation on the sensitivity to noradrenaline, its uptake and the termination of its action in isolated venous tissue. Naunyn-Schmiedebergs Arch. Pharmak. 271, 262–273 (1971).
Hellmann, G., Hertting, G., Peskar, B.: Effect of pretreatment with 6-hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart. Brit. J. Pharmacol. 41, 270–277 (1971).
Hughes, J.: Evaluation of mechanisms controlling the release and inactivation of the adrenergic transmitter in the rabbit portal vein and vas deferens. Brit. J. Pharmacol. 44, 472–491 (1972).
Hughes, J., Roth, R. H.: Evidence that angiotensin enhances transmitter release during sympathetic nerve stimulation. Brit. J. Pharmacol. 41, 239–255 (1971).
Iversen, L. L., Langer, S. Z.: Effects of phenoxybenzamine on the uptake and metabolism of noradrenaline in the rat heart and vas deferens. Brit. J. Pharmacol. 37, 627–637 (1969).
Iversen, L. L., Salt, P. J.: Inhibition of catecholamine Uptake2 by steroids in the isolated rat heart. Brit. J. Pharmacol. 40, 528–530 (1970).
Jacobowitz, D., Brus, R.: A study of extraneuronal uptake of norepinephrine in the perfused heart of the guinea-pig. Europ. J. Pharmacol. 15, 274–284 (1971).
Jarrott, B., Langer, S. Z.: Changes in monoamine oxidase and catechol-O-methyl transferase activities after denervation of the nictitating membrane of the cat. J. Physiol. (Lond.) 212, 549–559 (1971).
Kalsner, S., Nickerson, M.: Disposition of norepinephrine in vascular tissue, determined by the technique of oil immersion. J. Pharmacol. exp. Ther. 165, 152–165 (1969).
Kirpekar, S. M., Wakade, A. R., Prat, J. C.: Regeneration of sympathetic nerves to the vas deferens and spleen of the cat. J. Pharmacol. exp. Ther. 175, 197–205 (1970).
Lightman, S. L., Iversen, L. L.: The role of uptake2 in the extraneuronal metabolism of catecholamines in the isolated rat heart. Brit. J. Pharmacol. 37, 638–649 (1969).
Löffelholz, K., Lindmar, R., Muscholl, E.: Analysis of wash-out of noradrenaline from the perfused rabbit heart after infusion of noradrenaline. Naunyn-Schmiedebergs Arch. Pharmak. 270, R87 (1971).
Mayer, H. E., Abboud, F. M., Ballard, D. R., Eckstein, J. W.: Catecholamines in arteries and veins of the foreleg of the dog. Circulat. Res. 23, 653–661 (1968).
Osswald, W., Guimarães, S., Coimbra, A.: The termination of action of catecholamines in the isolated venous tissue of the dog. Naunyn-Schmiedebergs Arch. Pharmak. 269, 15–31 (1971).
Palmer, J. F.: The use of B-thiopropionic acid for the analysis of adrenaline and noradrenaline in plasma by the fluorimetric trihydroxindol method. W. Indian med. J. 13, 38–53 (1964).
Rolewicz, T. F., Whitmore, L., Zimmerman, B. G.: Transmitter release and response of arteries and veins to nerve stimulation. Amer. J. Physiol. 217, 1459–1463 (1969).
Spector, S., Tarver, J., Berkowitz, B.: Effects of drugs and physiological factors in the disposition of catecholamines in blood vessels. Pharmacol. Rev. 24, 191–202 (1972).
Starke, K., Montel, H., Schümann, H. J.: Influence of cocaine and phenoxybenzamine on noradrenaline uptake and release. Naunyn-Schmiedebergs Arch. Pharmak. 270, 210–214 (1971).
Su, C., Bevan, J. A.: The release of H3-norepinephrine in arterial strips studied by the technique of perfusion and transmural stimulation. J. Pharmacol. exp. Ther. 172, 62–68 (1970).
Trendelenburg, U.: Supersensitivity of the isolated nictitating membrane of the cat to sympathomimetic amines after impairment of the intraneuronal mechanisms of inactivation. Naunyn-Schmiedebergs Arch. Pharmak. 271, 29–58 (1971).
Trendelenburg, U., Draskóczy, P. R.: The effect of intraneuronal inactivation on the transmembranal uptake. J. Pharmacol. exp. Ther. 175, 521–524 (1970).
Vane, J. R.: The estimation of catecholamines by biological assay. Pharmacol. Rev. 18, 317–324 (1966).
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Osswald, W., Branco, D. The effects of drugs and denervation on removal and accumulation of noradrenaline in the perfused hind-limb of the dog. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 175–190 (1973). https://doi.org/10.1007/BF00501158
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DOI: https://doi.org/10.1007/BF00501158