Summary
The sensitivity of various isolated organs to catecholamines was tested before and after block of catechol-O-methyl transferase (COMT) by U-0521 (3′,4′-dihydroxy-2-methyl propiophenone; 18 μg/ml for 20 min).
Isolated Nictitating Membrane of the Cat. The sensitivity to catecholamines was increased by inhibition of COMT whenever the experimental conditions resulted in a high potency of the amine, i.e., when the ED50 of the amine (in the absence of U-0521) was below about 10−6 M. Thus, block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline after denervation (or in the presence of cocaine) but not on muscles with an intact adrenergic innervation; it also increased the sensitivity to theβ-effects but not to theα-effects of isoprenaline. No potentiation was observed for dopamine which has a low potency even after denervation. The relation between potency of the catecholamine and the degree of the sensitizing effect of U-0521 was not due to saturation of COMT or of access to the enzyme. Measurements in denervated muscles of the production of O-methylated metabolites from (±)-noradrenaline-H3 (added to the bath for 20 min in concentrations of about 10−7 to 10−4 M), and of the extraneuronal accumulation of noradrenaline-H3 did not reveal any saturation of either the enzyme or the extraneuronal accumulation of the amine.
When block of COMT resulted in supersensitivity to a catecholamine, the time required to reach steady-state responses was usually increased. This is consistent with the view that block of the enzyme impaired a site of loss.
Block of COMT failed to produce any substantial potentiation of the effects of the indirectly acting amines, tyramine and mephentermine. O-methylation of the released transmitter seems to occur after the amine has reached the receptors of the effector cells.
Isolated Strips of Cat and Bat Spleen. Results were quantitatively similar, since block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline in the presence but not (or only very little) in the absence of cocaine. However, the degree of supersensitivity after block of COMT (in the presence of cocaine) was smaller than in the nictitating membrane. In the cat spleen, cocaine causes a small but significant degree of supersensitivity to isoprenaline but not to methoxamine.
Isolated Sat Aorta, Block of COMT did not increase the effect of cocaine.
It is suggested that differences in the morphology of the adrenergic innervation contribute to the observed organ differences.
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With the technical assistance of Miss Roneen D. Hobbs.
This study was supported partly by Research Grant NB-07131 from the National Institutes of Health, U.S. Public Health Service, and partly by the Deutsche Forschungsgemeinschaft.
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Trendelenburg, U., Höhn, D., Graefe, K.H. et al. The influence of block of catechol-O-methyl transferase on the sensitivity of isolated organs to catecholamines. Naunyn-Schmiedebergs Arch. Pharmak. 271, 59–92 (1971). https://doi.org/10.1007/BF01002173
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DOI: https://doi.org/10.1007/BF01002173