Adenosine as an important mediator of post-ischaemic neuronal stunning.

See article by Burgdorf et al. [11] (pages 713 –720) in whereas the response to exogenous noradrenaline is unafthis issue. fected [9]. What is the mechanism behind neuronal stunning? It A brief period of ischaemia is known to induce a was initially suggested by Miyazaki and Zipes [8] that high prolonged period of reversible myocardial dysfunction potassium, low pH and adenosine each could inhibit despite normalized electrocardiogram and absence of sympathetic and vagal neurotransmission and contribute to histological signs of necrosis. This was first described by post-ischaemic neuronal dysfunction. It was subsequently Heyndrickx and co-workers [1] who found that myocardial demonstrated that administration of adenosine deaminase, function was depressed for several hours following a which lowers the levels of endogenous adenosine, pre15-min period of coronary artery occlusion in dogs. vented the attenuation in coronary vasoconstrictor response Braunwald and Kloner [2] subsequently named this pheto sympathetic nerve stimulation following ischaemia in nomenon ‘myocardial stunning’. Although the exact mechdogs [10]. These findings indicate that exogenous adenoanism underlying myocardial stunning is not fully undersine reduces cardiac neurotransmission and that endogenstood, results from several studies indicate that it can be ous adenosine is involved as a mediator of neuronal mediated by increased myocyte calcium levels and oxystunning. The role of adenosine has been further clarified gen-derived free radicals during ischaemia and the initial in the elegant study by Burgdorf et al. [11] in this issue of part of reperfusion [3–5]. Cardiovascular Research. In the isolated perfused rat heart, In addition to the reduced myocardial contractility, there the exocytotic release of noradrenaline induced by electriis also evidence of a long-lasting impairment of neurocal field stimulation was progressively suppressed by transmission in the post-ischaemic heart, a phenomenon increasing periods of ischaemia. In accordance with previknown as ‘neuronal stunning’. Martins et al. [6] demonous studies, both the degree and the duration of impaired strated that myocardial contractile function induced by noradrenaline release were dependent on the duration of sympathetic nerve stimulation was depressed in ischaemic ischaemia. A non-selective adenosine receptor antagonist myocardium. It was later described that the myocardial prevented the suppression of noradrenaline release when segment shortening evoked by sympathetic nerve stimulathe antagonist was given both during ischaemia and tion in dogs was markedly reduced following coronary reperfusion but not when it was given during reperfusion artery occlusion [7,8]. On the other hand, the response to only. This finding supports the concept that adenosine administration of exogenous noradrenaline was unaffected mediates the attenuation of noradrenaline release, and in by ischaemia, which indicates that the sympathetic neuroaddition demonstrates that this effect is mediated during transmission but not the post-junctional response to noradthe ischaemic period. Burgdorf and co-workers further renaline was impaired. Neuronal stunning affects not only show that the effect is mediated via activation of the myocardial contractile function but also regulation of the adenosine A receptor subtype since the suppressed norad1 coronary vasculature. The increase in coronary vascular renaline release was prevented by a selective adenosine A1 resistance evoked by sympathetic nerve stimulation is receptor antagonist but not by adenosine A or A receptor 2 3 markedly attenuated following coronary artery occlusion antagonists. The involvement of the adenosine A receptor 1 is further supported by the observation that a selective adenosine A receptor agonist, but not adenosine A or A *Tel.: 146-8-5177-5876; fax: 146-8-311-044. 1 2 3 E-mail address: [email protected] (J. Pernow). receptor agonists, suppressed noradrenaline release in