Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury.

Abstract

Morbidity and mortality from acute coronary artery occlusion may be reduced if local myocardial adenosine concentration is augmented because 1) coronary collateral blood flow during ischemia increases with adenosine infusion, and 2) granulocytes that accumulate in the microcirculation during ischemia are, to a large extent, inhibited by adenosine from generating superoxide anion free radicals, from adhering to vascular endothelium, and from damaging endothelial cells in culture. Using a cultured lymphoblast model system, we found that 5-amino-4-imidazole carboxamide (AICA) riboside enhanced adenosine accumulation during ATP catabolism. Therefore, AICA riboside pretreatment was used in canine myocardium to selectively increase adenosine concentration in the ischemic area during 1 hour of ischemia. At 5 minutes of ischemia, endocardial flow to ischemic myocardium in saline-treated and AICA riboside-treated dogs was 0.06±0.03 and 0.34±0.11 ml/min/g, respectively (p<0.01); flow to nonischemic myocardium was not affected. Ventricular tachycardia and premature ventricular depolarizations were significantly attenuated in the AICA riboside-treated dogs. Blood pressure and heart rate were not affected by AICA riboside. In venous blood from ischemic tissue, adenosine increased from undetectable levels (<0.01 ,M) to 0.22±0.08 ,uM in saline and 1.79±0.06 ,uM in AICA riboside-treated dogs, respectively (p<0.001). Coronary vein inosine concentrations were greater in saline than in AICA riboside-treated dogs. In separate in vitro studies, AICA riboside did not alter the removal rate of adenosine from canine blood. Indium-labeled granulocyte accumulation was significantly less in ischemic myocardium in AICA riboside-treated compared with saline-treated dogs. In addition, adenosine, but not AICA riboside, inhibited in vitro canine granulocyte superoxide production. We conclude that AICA riboside given before myocardial ischemia augments adenosine concentration, decreases arrhythmias, decreases granulocyte accumulation, and improves collateral flow to ischemic myocardium. One of the beneficial mechanisms could be an increased production of adenosine rather than inosine from ATP catabolism that causes vasodilation and inhibition of granulocytes. We propose a new hypothesis regarding regulation of the inflammatory reaction to ischemia in the microcirculation. Adenosine, in addition to its vasodilator action, is an anti-injury autacoid that links ATP catabolism to inhibition of granulocyte adherence, microvascular obstruction, and superoxide anion formation. (Circulation 1989;80:1400-1411 *All editorial decisions for this article, including selection of reviewers and the final decision, were made by a guest editor. This procedure applies to all manuscripts with authors from the

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

“…One clear difference in activity between adenosine and acadesine is the accompanying hemodynamic changes. Acadesine is hemodynamically "silent" because it does not increase adenosine levels in the systemic circulation but, rather, augments local adenosine levels in situations where adenosine production is increased, e.g., during myocardial ischemia (13). 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.…”

“…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).…”

“…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.…”

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

“…changes in intracellular adenine nucleotide levels or inhibition of adenosine transport) [49], we next generated adenoviral vectors to explore the effects of active or inactive forms of AMPKα1. Expressed in MIN6 cells at an optimal multiplicity of infection ($ 30 infectious units\cell or above), each adenovirus led to 90 % transduction of MIN6 cells (as assessed through the expression of eGFP) and the synthesis of c-Myc-tagged proteins at the molecular masses predicted for AMPK CA (31 kDa) or AMPK DN (63 kDa) [13] ( Figure 3D).…”