Acadesine: Prototype adenosine regulating agent for treating myocardial ischemia‐reperfusion injury

Abstract

Acadesine is an adenosine regulating agent currently being developed for treatment of ischemia-reperfusion injury in the setting of cardiac surgery. While the cardioprotective effects of adenosine are well recognized, the intrinsic hemodynamic and cardiac effects of adenosine limit its potential usefulness as a therapeutic agent. In contrast, acadesine has been shown to elevate endogenous levels of adenosine during periods of ischemia without exhibiting systemic hemodynamic actions. The site-specific and event-specific mechanism of action thus provides cardioprotection without the adverse sequelae commonly observed with adenosine. This review describes the pertinent literature which establishes acadesine's action as an adenosine regulating agent, and discusses past and recent studies which focus on the cardioprotective actions of acadesine. These studies include in vitro and in vivo models of regional and global ischemia, and models of cardiac surgery. Aspects of dose-response, timing of administration, and pharmacokinetics of acadesine are described which reconcile prior controversy regarding acadesine's cardioprotective actions. These studies, taken together, demonstrate that acadesine is the prototype of a new class of adenosine regulating agents useful as therapy for cardiac ischemia. o 1993 WiIey-Liss, Inc.

Adenosine-mediated inhibition of platelet aggregation by acadesine. A novel antithrombotic mechanism in vitro and in vivo.

“…The decrease in coronary perfusion pressure secondary to hypotension elicited by adenosine and dipyridamole could act to reduce the shear stress in the stenotic vessel, which normally helps to dislodge the thrombus and thus offsets any antithrombotic activity. In addition, adenosine and dipyridamole are potent coronary vasodilators, in contrast to acadesine (13,18). The former two agents are used to provoke coronary steal to aid in the diagnosis of ischemic heart disease using thallium scintigraphy (48).…”

“…The nucleoside analog, acadesine, has received attention recently as a means of protecting the myocardium during ischemia and reperfusion in animal models (13)(14)(15)(16)(17)(18) and during coronary artery bypass graft surgery in patients (19,20). Preclinical data indicate that this action is due to enhanced extracellular adenosine levels during ischemia (13,21,22).…”

“…While the exact mechanism of the adenosine-regulating action is not understood, acadesine is taken up by cells and phosphorylated by adenosine kinase to its monophosphate, ZMP 1 (23, 24, Fig. 1), and both acadesine and ZMP can inhibit enzymes involved in adenosine metabolism and formation, respectively, to augment extracellular adenosine levels during ischemia (18). In view of this adenosine-regulating activity of acadesine, and the proposed antiplatelet activity of adenosine, the present studies were undertaken to (a) evaluate the effects of acadesine on platelet aggregation in vitro, ex vivo, and in vivo; (b) assess the involvement of adenosine in mediating the effects of acadesine on platelet aggregation; and (c) compare the antiaggregatory effects of acadesine to those observed with exogenously administered adenosine and dipyridamole.…”

“…18 and 28 kg were used in these studies. Dogs were fasted overnight, sedated with acepromazine (1 mg/kg, i.m.…”

Mind over Matter - Regulation of Peripheral Inflammation by the CNS

“…Such observations suggest that a number of agents may elevate tissue levels of adenosine primarily in stressed or inflamed conditions. This concept has been termed "site and event specifity" when it has arisen in other contexts [109,110], and it may be particularly important in inflammation where a dampening of provoked responses, rather than a more complete inhibition of responses, would be desirable [75]. In endothelial cells, the increase in extracellular levels of adenosine produced by methotrexate originates as nucleotide, as it is markedly reduced by inhibition of ecto-5' -nucleotidase and is not observed from cells deficient in ecto-5' -nucleotidase; this likely represents a modulation of nucleotide metabolism and a non-exocytotic release from such cells [1081.…”