Cellular and molecular mechanism(s) of coronary flow regulation by adenosine.

Abstract

There is strong evidence in favor of a major role for adenosine in the metabolic regulation of blood flow to the heart. The exact nature of the molecular and cellular events leading to the vasodilatation by adenosine are poorly understood. In the present report we have provided experimental evidence that; (i) hypoxia of cardiac cells resulted in the production of adenosine (and its degradative products) which can be responsible for the hypoxic dilation observed by several workers; (ii) the release of metabolites such as potassium and inorganic phosphate was unchanged due to a 30-minute hypoxia of cardiac cells; (iii) the release of prostaglandin E but not F was enhanced due to hypoxia of cardiac cells which may be due to the storage pools in the cells; (iv) prostaglandin E1, E2 and F2 alpha inhibited the uptake of adenosine at pharmacological concentrations but not at physiological concentrations; (v) prostaglandin synthetase inhibitors (aspirin and indomethacin) nonspecifically inhibited the uptake of adenosine in the cardiac cells; (vi) lowering of pH resulted in inhibition in the uptake of adenosine and its incorporation into adenine nucleotides in cardiac cells; (vii) lowering the pH of the perfusion medium resulted in the increased release of perfusate adenosine (and its degradative products) with a simultaneous increase in coronary blood flow; (ix) specific adenosine receptor sites were found in cardiac muscle, coronary arteries, and carotid arteries of the dog and rabbit aorta, which satisfy the basic characteristic of receptor binding; and (x) these receptor binding sites were different from the adenosine uptake protein and were competitively blocked by theophylline or aminophylline. It is concluded that adensine plays a major role in blood flow regulation to the heart and acts through specific receptors to produce vasodilatation.