Summary
Ischemia induces a nonexocytotic noradrenaline release in the heart, which leads to high and potentially harmful interstitial noradrenaline concentrations. The effect of beta-adenoceptor antagonists on noradrenaline release in ischemia has been investigated in the present study.
DL-Propranolol (1–100 μmol/l) concentration-dependently reduced noradrenaline release during 20 min of global and total ischemia in the perfused rat heart. Other beta-adrenoceptor blocking agents such as atenolol, metoprolol, and timolol (10 μmol/l each), however, did not share this effect. Moreover, both stereoisomers of propranolol were equipotent in suppression of ischemia-induced noradrenaline release, indicating a property of propranolol independent from interaction with beta-adrenoceptors. The well known local anesthetic action of propranolol was not likely to cause its inhibitory effect on ischemia-induced noradrenaline release, as lidocaine (10 μmol/l) did not affect noradrenaline overflow in ischemia. The effect of propranolol was further examined in cyanide intoxication, an experimental model of energy depletion. In this experimental setting the release of dihydroxyphenylethyleneglycol - the major neuronal metabolite of noradrenaline - served as indicator of increased axoplasmic noradrenaline levels which are present during nonexocytotic noradrenaline release. In cyanide intoxication DL-propranolol also reduced noradrenaline overflow but did not affect release of dihydroxyphenylethylene glycol. The latter finding suggests an interaction of propranolol with the neuronal membrane transport of noradrenaline. In ischemia and cyanide intoxication, transport of noradrenaline across the plasma membrane is known to be driven by the noradrenaline carrier (uptake,) working in reverse of its normal direction - from inside to outside. Consequently, inhibitors of the noradrenaline carrier like desipramine were shown to suppress nonexocytotic noradrenaline release in ischemia and cyanide intoxication. In order to test the ability of propranolol to interact with the noradrenaline carrier a model of 3H-noradrenaline uptake was employed in normoxic rat heart. DL-Propranolol concentration-dependently (1–100 μmmol/l) inhibited 3H-noradrenaline uptake, while atenolol and timolol did not interfere with 3H-noradrenaline uptake.
In conclusion, the results indicate suppression of noradrenaline release in myocardial ischemia by propranolol. This action of propranolol is independent of its beta-adrenoceptor blocking properties and is rather due to an interaction of propranolol with the neuronal noradrenaline transport mechanism (uptake1).
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The work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 320 - Cardiac Function and its Regulation)
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Richardt, G., Lumpp, U., Haass, M. et al. Propranolol inhibits nonexocytotic noradrenaline release in myocardial ischemia. Naunyn-Schmiedeberg's Arch Pharmacol 341, 50–55 (1990). https://doi.org/10.1007/BF00195057
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DOI: https://doi.org/10.1007/BF00195057