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Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes,
H E Gruber1, M E Hoffer, D R McAllister
1Arthritis/Biochemical Genetics Division, University of California, San Diego.
Insights
Pretreating with 5-amino-4-imidazole carboxamide (AICA) riboside increases adenosine levels during myocardial ischemia. This improves collateral blood flow and reduces arrhythmias and granulocyte accumulation in the ischemic heart.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Cellular Biology
Background:
- Acute coronary artery occlusion leads to myocardial damage.
- Adenosine plays a protective role by increasing collateral blood flow and inhibiting granulocyte-mediated injury.
- Augmenting local adenosine concentration may reduce ischemia-induced morbidity and mortality.
Purpose of the Study:
- To investigate if 5-amino-4-imidazole carboxamide (AICA) riboside pretreatment can increase myocardial adenosine concentration during ischemia.
- To evaluate the effects of AICA riboside on collateral blood flow, arrhythmias, and granulocyte accumulation in ischemic myocardium.
- To explore the underlying mechanisms of AICA riboside's protective effects.
Main Methods:
- Canine model of 1-hour myocardial ischemia.
- Administration of AICA riboside or saline as pretreatment.
- Measurement of myocardial blood flow, electrocardiographic activity, and adenosine/inosine levels.
- Assessment of indium-labeled granulocyte accumulation and in vitro granulocyte superoxide production.
Main Results:
- AICA riboside significantly increased adenosine levels in ischemic myocardium compared to saline controls.
- Endocardial collateral blood flow was markedly enhanced in AICA riboside-treated dogs.
- Ventricular arrhythmias were significantly attenuated, and granulocyte accumulation was reduced in the AICA riboside group.
- AICA riboside did not affect blood pressure or heart rate.
Conclusions:
- AICA riboside effectively augments adenosine concentration in the ischemic myocardium.
- Pretreatment with AICA riboside demonstrates cardioprotective effects by improving collateral flow and reducing ischemia-induced arrhythmias and inflammation.
- The findings suggest AICA riboside-mediated adenosine increase is a promising therapeutic strategy for acute myocardial ischemia.
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.