Synthesis, Binding, Release, and Metabolism of Norepinephrine in Normal and Transplanted Dog Hearts

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Abstract
The ability of normal and transplanted dog hearts to make, bind, store, and metabolize norepinephrine was studied. Transplanted hearts were used in order to assess the effects of adrenergic denervation. Normal hearts bound large quantities of administered C14-dopamine and synthesized considerable quantities of norepinephrine in both the atria and ventricles. Isolated perfused normal hearts steadily removed about 56% of infused dl-H3-norepinephrine; a binding mechanism was the major means of inactivation of the amine. Uptake of radioactive norepinephrine was greater in the ventricles than in the atria because they received more of the amine, and the turnover rate of the labeled amine was also highest in the ventricles. Subcellular fractionation of the bound amine demonstrated that it was localized in particles of microsomal size; radioautographic studies demonstrated the presence of H3-norepinephrine only in association with nerves. About 57% of the H3-norepinephrine released from normal hearts was metabolized, primarily by O-methylation. After autotransplantation, and degeneration of postganglionic sympathetic nerves, the average catecholamine content of the hearts fell to 1.2% of normal, C14-dopamine uptake and formation of norepinephrine were reduced to a few per cent of normal, and the uptake and retention of H3-norepinephrine was 6.1% of normal under the conditions used. Binding of norepinephrine to unknown sites in the transplanted tissue served temporarily as an important mechanism of inactivation of the amine, but this norepinephrine was very rapidly released and nearly 85% metabolized, again predominantly by O-methylation. The fine structure of the transplanted tissues was barely distinguishable from that of normal hearts by electron microscopy. In vitro assays of catechol-O-methyltransferase and monoamine oxidase showed little change in activity upon adrenergic denervation. These results demonstrate the importance of the adrenergic innervation of the heart for the normal synthesis, storage and inactivation of norepinephrine.