Key result
Blockade of extraneuronal accumulation of catecholamines potentiated both metabolic and mechanical beta-adrenoceptor-mediated responses of the isolated rat heart to isoprenaline.
Why the study?
Does blockade of extraneuronal uptake alter metabolic and mechanical responses to isoprenaline in isolated rat hearts?
Does blockade of extraneuronal uptake alter metabolic and mechanical responses to isoprenaline in isolated rat hearts?
Blockade of extraneuronal catecholamine uptake potentiates metabolic and mechanical beta-adrenoceptor responses to isoprenaline in the rat heart, suggesting Uptake2 and beta-adrenoceptors are separate entities.
Should not change clinical catecholamine management; leaves open whether Uptake2 blockade augments beta-responses in human myocardium.
Isolated rat hearts accumulated 102 pmol/g wet wt/min of isoprenaline when perfused for 5 min with 0-6 muM (+/-)-3H-isoprenaline. 2. The 3-methoxy derivative of isoprenaline ('methoxy isoprenaline') (10 muM) significantly inhibited this uptake by 57%, metanephrine (10 muM) by 29% and normetanephrine (10 muM) by 21%. 3. (+/-)-Isoprenaline (0-6 muM) infused into isolated perfused rat hearts for 5 min activated glycogen phosphorylase 2-4-fold. Normetanephrine (10 muM) or metanephrine (10 muM included in the perfusate significantly potentiated this activation, but 3-0-methyl isoprenaline (10 muM significantly reduced it. However, 3-0-methyl isoprenaline potentiated the ability of 4-8 muM isoprenaline to stimulate phosphorylase. 4. Neither metanephrine (10 muM) nor normetanephrine (10 muM) altered peak inotropic responses to injections of (+/-)-isoprenaline into the solution perfusing isolated rat hearts. 3-0-methyl isoprenaline (10 muM) shifted the isoprenaline dose-response curve to the right, but did not affect the inotropic responses to CaCl2, confirming that 3-0-methyl isoprenaline possess beta-adrenoceptor antagonist activity. 5. Inotropic responses to isoprenaline were significantly prolonged by both 3-0-methyl isoprenaline and normetanephrine (10 muM). 6. These results indicate that blockade of extraneuronal accumulation of catecholamines causes potentiation of both metabolic and mechanical beta-adrenoceptor-mediated responses of the heart to isoprenaline. It is suggested that Uptake2 and the cardiac beta-adrenoceptor are separate entities, and that the beta-adrenoceptor is localized in the sarcolemma. The physiological function of Uptake2 may be to help clear the sympathetic synaptic gap of liberated neurotransmitter.
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Picken et al. (1975) studied this question. Blockade of extraneuronal uptake (methoxy isoprenaline, metanephrine, normetanephrine) was evaluated on Isoprenaline uptake and glycogen phosphorylase activation. Blockade of extraneuronal accumulation of catecholamines potentiated both metabolic and mechanical beta-adrenoceptor-mediated responses of the isolated rat heart to isoprenaline.