Inhibition of adenosine-mediated coronary vasodilation exacerbates myocardial ischemia during exercise

Abstract

Persisting coronary vasoconstrictor tone that is responsive to exogenous adenosine administration has been demonstrated during myocardial ischemia. Therefore, the role and extent of endogenous adenosine-mediated coronary vasodilation in opposing coronary vasoconstriction within regions of ischemic myocardium was investigated in 10 chronically instrumented exercising dogs. Studies were performed on dogs with left circumflex coronary artery stenosis during treadmill exercise (6.5 km/h, 6% grade), while myocardial blood flow was measured with radioactive microspheres. Blood flow was measured before and again after inhibition of the effects of endogenously produced adenosine through combined inactivation of adenosine and adenosine receptor antagonism by the administration of intracoronary adenosine deaminase (ADA) (5 micrograms.kg-1 x min-1 x 10 min) plus 8-phenyltheophylline (8-PT) (5 mg/kg i.v.), respectively. Coronary perfusion pressure was held equal during both conditions at approximately 41 mmHg with a hydraulic occluder. During exercise in the presence of a coronary stenosis, blood flow was reduced in all layers of myocardium in regions supplied by the stenosed left circumflex coronary artery compared with blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery. After ADA plus 8-PT, myocardial blood flow (in ml.min-1 x g-1) was further reduced in all layers of myocardium in regions supplied by the stenotic left circumflex coronary artery compared with baseline (subendocardial layer 0.44 +/- 0.09 vs. 0.67 +/- 0.13 ml.min-1 x g-1, mean transmural flow 0.92 +/- 0.13 vs. 1.25 +/- 0.2 ml.min-1 x g-1, both P < 0.05). Blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery were unchanged following ADA plus 8-PT.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

“…Gallagher et al (37) demonstrated that full wall thickening depends on subendocardial perfusion and correlates poorly with subepicardial perfusion, suggesting that the decreases in blood flow produced by glibenclamide and 8-phenyltheophylline in the present study, which were paralleled by decreases in systolic wall thickening, were also present in the innermost layers. This is also supported by our previous studies that demonstrated that adenosine receptor blockade aggravates hypoperfusion in all myocardial layers distal to a coronary artery stenosis during exercise (4,5). The observation in the present study that, after K ϩ ATP channel blockade with glibenclamide, systolic wall thickening was depressed proportionally more than coronary artery blood flow could be interpreted to suggest that a nonuniform blood flow distribution could have occurred with a more prominent decrease in subendocardial than in subepicardial blood flow.…”

“…In contrast, when coronary pressure was reduced, adenosine blockade significantly decreased blood flow during exercise. Similarly, adenosine receptor blockade has been previously reported to decrease coronary blood flow distal to a coronary artery stenosis (4,5). These findings suggest that reductions of coronary artery pressure sufficient to cause myocardial hypoperfusion result in augmented adenosine production, which contributes to coronary vasodilation.…”

“…Optimal curve fitting of the coronary pressure-flow and pressure-function data was obtained with a fourth-order polynomial (y ϭ a ϩ bx ϩ cx 2 ϩ dx 3 ϩ ex 4 ), and coronary flows were computed at several coronary pressures within the range of coronary pressures measured during each protocol.…”

“…In contrast, these vasodilator mechanisms can contribute significantly to regulation of coronary vasomotor tone during exercise in the presence of myocardial hypoperfusion. Thus, blockade of adenosine (4,5) or nitric oxide (6) decreased coronary blood flow distal to a coronary artery stenosis that resulted in myocardial hypoperfusion during exercise.…”

Changes in pH Increase Perfusion Pressure of Coronary Arteries in the Rat

“…Adenosine is an important metabolite involved in vasodilation, and is released from various tissues as an endogenous protective agent in ischemia (41 -43). It has been reported that endogenous adenosine contributes significantly to coronary vasodilation during ischemia (44). ATP-sensitive K + channel activation may play an important role in adenosine-induced vasodilation (42,45).…”