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Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine

Nachdem elektronenmikroskopische Untersuchungen gezeigt hatten, daß 6-OH-DA selektiv die peripheren adrenergen Nervenendigungen zerstört, wurde untersucht, welche Beziehungen zwischen der dosisabhängigen Senkung des Noradrenalingehaltes durch 6-OH-DA und dessen Aufnahme und Speicherung in sympathisch innervierten Organen besteht und ob 6-OH-DA zu einer generellen chemischen Sympathektomie benützt werden kann.

Nach Verabreichung von 1 mg/kg 6-OH-DA intravenös war der Noradrenalingehalt in Herz und Milz der Ratte nur kurzfristig (Ausgangswert nach 24 Std wieder erreicht) gesenkt, nach 30 mg/kg dagegen zeigte die Senkung des Noradrenalingehaltes während einer Woche keine Rückbildungstendenz. Nach Verabreichung von 1 mg/kg ³H-6-OH-DA intravenös war das fehlende Noradrenalin mehr als stöchiometrisch durch ³H-Amine ersetzt, nach 30 mg/kg dagegen fanden sich bei stärkerer Senkung des Noradrenalingehaltes nach 2 Std nur noch geringe Mengen, nach 24 Std überhaupt keine ³H-Amine mehr. Bei Verabreichung kleiner Dosen von 6-OH-DA wird dieses offenbar in den sympathischen Nerven gespeichert und kann als falscher Transmitter freigesetzt werden (Nachweis an der isolierten Milz der Katze). Hohe Dosen dagegen zerstören die adrenergen Nervenendigungen und damit ihre eigenen Aminspeicher.

Die vollständigste chemische Sympathektomie an Ratten wurde erzielt, wenn die Tiere innerhalb 24 Std mit 2×34 mg/kg und eine Woche später mit 2×68 mg/kg 6-OH-DA intravenös behandelt wurden. Eine Woche nach der letzten Dosis betrug der Noradrenalingehalt im Herzen 7,6%, in der Milz 5,1% und im Vas deferens 18,8% des Gehaltes entsprechender Kontrollen. Nach 2 Wochen war der Noradrenalingehalt nicht oder nur unbedeutend angestiegen, nach 4 Wochen hingegen fand sich in allen Organen eine eindeutige Anstiegstendenz.

Die Aufnahme von ³H-Noradrenalin war ungefähr im gleichen Maße vermindert wie der Gehalt an endogenem Noradrenalin.

Wurden Katzen mit 2×14 und 2×34 mg/kg 6-OH-DA intravenös behandelt, so betrug eine Woche nach Verabreichung der letzten Dosis der Noradrenalingehalt im Herzen 2,8%, in der Milz 3,1%, in der Nickhaut 8,3% und in der Iris 2,8% des Gehaltes unbehandelter Kontrollen.

Die chemische Sympathektomie mit 6-OH-DA ist in ihrer Wirksamkeit der chirurgischen Denervation und der Immunosympathektomie ebenbürtig, z. T. auch überlegen, doch sind auch hier Organ- und Speziesunterschiede vorhanden.

After electronmicroscope studies had shown that 6-hydroxydopamine (6-OH-DA) induced a selective destruction of adrenergic nerve terminals, we studied the correlation between the dose-dependent norepinephrine depletion by 6-OH-DA and its uptake and storage in sympathetically innervated organs. We also investigated whether 6-OH-DA can be used for general chemical sympathectomy.

Whereas the intravenous administration of 1 mg/kg of 6-OH-DA caused only a temporary drop in the norepinephrine content of the rat heart and spleen (original values were regained after 24 hr), 30 mg/kg provoked a norepinephrine depletion which showed no signs of recovery for up to a week. Following the intravenous administration of 1 mg/kg of ³H-6-OH-DA, the norepinephrine missing in sympathetically innervated organs was more than stoichiometrically replaced by ³H-amines, whereas in the case of 30 mg/kg of ³H-6-OH-DA after 2 hr only very small quantities of ³H-amines could be detected, and after 24 hr none at all. It seems that after administration of low doses 6-OH-DA is stored in sympathetic nerves and can be liberated as a false transmitter (as shown in the isolated cat spleen). Higher doses, however, lead to a destruction of adrenergic nerve endings and consequently to a destruction of their own amine stores as well.

The most complete chemical sympathectomy in rats could be achieved when animals were treated intravenously with 2×34 mg/kg within a 24 hr period and a week later with 2×68 mg/kg. A week after the last dose of 6-OH-DA the norepinephrine level in the heart amounted to 7.6%, in the spleen to 5.1% and in the vas deferens to 18.8% of the level in corresponding control animals. The uptake of intravenously injected ³H-norepinephrine was reduced to approximately the same extent as the endogenous norepinephrine content.

In cats pretreated with 2×14 and 2×34 mg/kg of 6-OH-DA intravenously, one week after the last dose of 6-OH-DA the norepinephrine content in the heart amounted to 2.8%, in the spleen to 3.1%, in the nictitating membrane to 8.3% and in the iris to 2.8% of that of untreated controls.

Chemical sympathectomy with 6-OH-DA compares favourably with surgical denervation or immunosympathectomy, but with this method, too, considerable differences between species and organs occur.

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1. Department of Experimental Medicine, F. Hoffmann-La Roche & Co. Ltd., Basle, Switzerland

   H. Thoenen & J. P. Tranzer

1. H. Thoenen
2. J. P. Tranzer

Preliminary results of this report have been communicated to the German Pharmacological Society in Mainz at the Spring Meeting 1968.

Thoenen, H., Tranzer, J.P. Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedebergs Arch. Pharmak. u. Exp. Path. 261, 271–288 (1968). https://doi.org/10.1007/BF00536990

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• Received: 29 May 1968

• Issue Date: January 1968

• DOI: https://doi.org/10.1007/BF00536990

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