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 less than 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 (less than 0.01 microM) to 0.22 +/- 0.08 microM in saline and 1.79 +/- 0.06 microM in AICA riboside-treated dogs, respectively (p less than 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.