Diminished effect of sympathetic nerve stimulation in cats pretreated with 5-hydroxydopa; formation and liberation of false adrenergic transmitters.

Abstract

Pretreatment of cats with 5-hydroxydopa (3×200 mg/kg i.p., given over a period of 28 hours) resulted in a marked depletion of norepinephrine in sympathetically innervated organs (heart 5%, spleen 3%, iris 16% and nictitating membrane 12% of controls) and in a greatly diminished response of the spleen and nictitating membrane to sympathetic nerve stimulation. The decreased contractile response of the isolated perfused spleen was accompanied by a corresponding diminution of the norepinephrine output. The effect of intravenously injected norepinephrine on the blood pressure and nictitating membrane did not differ significantly from that of untreated controls. The chromatographic analysis of amines present in the spleen and heart after administration of 5-hydroxydopa and [3H]5-hydroxydopamine revealed the accumulation of 5-hydroxydopamine, of two not yet definitely identified β-hydroxylated metabolites (most probably the β-hydroxylated derivatives of 5-hydroxydopamine and of one of its O-methylated metabolites) and three O-methylated derivatives chromatographically identified as 4-methoxy-3,5-dihydroxyphenethylamine, 3-methoxy-4,5-dihydroxyphenethylamine and 3,4-dimethoxy-5-hydroxyphenethylamine. 5-Hydroxydopamine, its two β-hydroxylated and its two monomethoxylated metabolites were liberated as sympathetic transmitters. Their “direct” sympathomimetic effect (the β-hydroxylated derivatives were not available as references) on the nictitating membrane and spleen was 300–10000 times weaker than that of norepinephrine. It is concluded that the diminished contractile response of the nictitating membrane and spleen to sympathetic nerve stimulation results from a reduction of the physiological transmitter available for liberation and its replacement by less potent transmitter substances.