Relative importance of neuronal and extraneuronal mechanisms for the uptake and retention of noradrenaline in different tissues of the rat

Summary

The retention of total radioactivity or³H-noradrenaline (³]H-NA) and in some experiments also its metabolites after administration of (±)-³H-NA was studied in rat hearts and salivary glandsin vitro andin vivo. Intact, atrophied and postganglionically sympathectomized (chronically denervated) glands were used. Protriptyline was administered to interfere with the neuronal amine uptake mechanism. In order to study the possible influence of amine catabolizing enzymes,³H-metaraminol was also used as substratein vitro. At a low³H-NA concentration about equal amounts of radioactivity were retained by intact and atrophied salivary gland slices and by heart slicesin vitro, while in the denervated gland smaller amounts were recovered. By increasing the³H-NA concentration significantly lower amounts of radioactive material were retained in the atrophied than in the intact salivary gland slices, indicating a reduced extraneuronal binding in the atrophied gland tissue.In vitro administration of protriptyline in different concentrations inhibited the retention of radioactivity in heart and atrophied salivary gland slices to about the same extent, while in intact salivary gland slices the effect of the drug was much less pronounced. The difference persisted after using maximally effectives protriptyline concentrations, and was attributed to the high level of NA catabolites, especially normetanephrine (NM), found in the intact glands after protriptyline. When this drug was administeredin vivo in low doses the effect was less pronounced in the atrophied gland slices than in the intact ones. As this difference disappeared when higher doses of protriptyline was administered, it was interpreted as a result of an unequal distribution of the drug by the blood flow.

Maximally effective doses of protriptyline exerted at greater effect on the accumulation of total radioactivityin vivo in hearts than in salivary glands.³H-NA, however, was reduced to about the same low level in hearts as in intact salivary glands. A high amount of⁸H-NM in the intact glands explains this difference. Certain differences in the dose-response relationship for protriptyline between the different organs were observed, which might be attributed to differences in blood flow.

Also when³H-metaraminol was used as substrate, protriptyline, when given bothin vitro andin vivo, reduced the amine retention to a greater extent in atrophied salivary gland slices than in intact ones. Since in this case an influence of monoamine oxidase and catechol-O-methyl transferase can be excluded the data point to the importance of a parenchymal uptake mechanism for amine retention.