The distribution of 3H-isoprenaline in the perfused rat heart was re-examined. After initial loading with 3H-isoprenaline hearts were washed out with amine-free solution; the efflux curves were subjected to the peeling technique, and half times for efflux and compartment sizes were determined. In contrast to earlier reports from his department (Bönisch et al. 1974;l Bönisch 1978), 3H-isoprenaline was found to distribute mainly into one extra-neuronal compartment, irrespective of whether COMT was intact or inhibited (by the presence of U-0521). It was also not influenced by pretreatment of the animals with reserpine. This type of distribution was influenced neither by the concentration of isoprenaline nor by the duration of the loading of the tissue with the amine. The one major extra-neuronal distribution compartment of 3H-isoprenaline has the characteristics of the "old" compartment III: it has a relatively short half time for the efflux of 3H-isoprenaline and it has a high activity of COMT. Moreover, corticosterone inhibits the inward and outward flux of 3H-isoprenaline into and from compartment III. The Ki for the inhibition by corticosterone of the efflux of 3H-isoprenaline (2 mumol/l) is very similar to the Ki for impairment of uptake2 (determined by Bönisch 1978). Apart from the major distribution compartment III, two minor distribution compartments were detected: On the one hand, experiments with hearts which had an intact COMT revealed that a minor distribution compartment IV (characterized by a long half time for efflux and by an absence of COMT activity) may exist, although its magnitude does not exceed one tenth of the former compartment IV. In addition, part of the quickly equilibrating (and rather small) compartment II was corticosterone-sensitive. When the results of Azevedo et al. (1983 are considered together with the present results, compartment III appears to represent the uptake of 3H-isoprenaline into myocardial cells, while it is likely that radioactivity accumulated in the smooth muscle of blood vessels may constitute the corticosterone-sensitive part of compartment II.

The neuronal and extraneuronal uptake and deamination of 3H-(-)-phenylephrine was studied in perfused rat hearts obtained from reserpine-pretreated animals. 1. Under the conditions of steady-state perfusion with 5 mumol/l 3H-(-)-phenylephrine slightly more than 50% of total deamination took place in adrenergic nerve endings, slightly less than 50% in the extraneuronal tissue. 2. 3H-(-)-phenylephrine is preferentially deaminated to the glycol metabolite. 3. There is pronounced non-saturable, cocaine- and corticosterone-resistant uptake of 3H-(-)-phenylephrine in the perfused rat heart. 4. The apparent rate constants for the efflux of the glycol metabolite is about 20 times higher than that for the efflux of the acid metabolite. 5. For both the glycol and the acid metabolite of 3H-(-)-phenylephrine, apparent rate constants for the efflux declined when the duration of the perfusion with the labelled parent amine was prolonged. This phenomenon was also observed when the deamination of 3H-(-)-phenylephrine was restricted to either the adrenergic nerve endings or the extraneuronal tissue. These results are interpreted as evidence for a distribution of each metabolite into at least two kinetically different compartments. 6. This was confirmed for the acid metabolite by determination of a biphasic efflux curve in wash-out experiments in which MAO was inhibited during wash-out (after an initial loading of the adrenergic nerve endings with 3H-(-)-phenylephrine).

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It has been postulated that propranolol lowers the intraocular pressure by adrenergic neurone block. However, in the isolated iris of albino rabbits, there was only a small degree of cocaine-sensitive (i.e., neuronal) accumulation of 3H-(-)-propranolol, and none at all after pretreatment of the animals with reserpine. Moreover, after preloading of the iris with 3H-(-)-propranolol, veratridine failed to release any labelled material. Hence, any adrenergic neurone blocking action of propranolol is highly unlikely. Albino and pigmented irides were first exposed to 3H-(-)-propranolol and then washed out. The results and their compartmental analysis indicated an extensive binding of 3H-(-)-propranolol in or at pigment cells; the binding is characterized by a low dissociation constant. It is very likely that the initial binding and the subsequent slow dissociation from pigment cells explains the long duration of action of beta-adrenoceptor antagonists in human therapy.

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