Correlation between desipramine levels and (—)‐noradrenaline uptake and chronotropic effect in isolated atria of rats

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Abstract
1 The uptake of unlabelled and [14C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 μg/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2–3 h of incubation unless concentrations of desipramine higher than 1 μg/ml were used. 2 The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration. 3 The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria. 4 The inhibition of (—)-noradrenaline uptake and the potentiation of the chronotropic response to (—)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 001 to 1 μg/g. Higher tissue levels show less potentiation of the effect of (—)-noradrenaline or even inhibition of the maximal response to (—)-noradrenaline. These concentrations of desipramine (> 7 μg/g) markedly depressed the atrial rate. 5 The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.

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