Effects of Intravenous and Intracoronary Adenosine 5′-Triphosphate as Compared With Adenosine on Coronary Flow and Pressure Dynamics
To the Editor:
Recently, Jeremias et al1 reported their studies comparing the vasodilator action of intracoronary injected adenosine with ATP in 6 healthy mongrel dogs. On the basis of a dose-response curve ranging from 10 to 100 μg, the authors conclude that adenosine and ATP are approximately equipotent vasodilators. Neither substance could induce maximal vasodilation, as assessed with postischemic hyperemia. Similar results were obtained by Kato et al2 in the human coronary vasculature using a single dose of adenosine and ATP (20 μg), without comparison with postischemic hyperemia. Both groups conclude that adenosine and ATP are equipotent coronary vasodilators and suggest that the ATP-induced vasodilation is caused by its degradation to AMP and adenosine, with subsequent stimulation of adenosine A2 receptors. We disagree their conclusions for the following 2 reasons:
1. Equimolar doses of ATP and adenosine should be compared. The molecular weight of ATP is roughly twice that of adenosine (551.15 g versus 267.24 g). As shown in Figure 1 from the article by Jeremias et al,1 the response to 20, 40, and 100 μg ATP differed significantly from that of approximately equimolar doses of adenosine (10, 20, and 50 μg, respectively) in favor of ATP.
2. Jeremias et al1 did not study the maximal effect of intracoronary adenosine or ATP. Their last dose step from 60 to 100 μg significantly increased vasodilation. Therefore, these data do not exclude the possibility that dose escalation of ATP or adenosine would have resulted in a further increase in vasodilation.
We addressed these questions in the human forearm3 and observed that ATP is a more potent vasodilator than adenosine at equimolar doses. Theophylline, a purinergic P1 receptor antagonist, did not significantly inhibit ATP-induced forearm vasodilation. Therefore, we concluded that ATP-induced vasodilation is not mediated by its metabolites AMP or adenosine; instead, the P2y receptor is most likely involved. In our view, these observations are supported by Jeremias et al1 in the canine coronary circulation. Furthermore, we explored the maximal vasodilator effect of ATP in the human forearm and found that ATP induces maximal vasodilation, as determined with postischemic hyperemia.3 In conclusion, we want to emphasize the importance of the use of equimolar doses of agonists when their vasodilator potencies are compared. Furthermore, the maximal vasodilator action of ATP or adenosine should be determined before it can be concluded that “maximal hyperemia was not achieved by either pharmacological stimulus.”1
- Copyright © 2001 by American Heart Association
Jeremias A, Filardo SD, Whitbourn RJ, et al. Effects of intravenous and intracoronary adenosine 5′-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation. 2000;101:318–323.
Rongen GA, Smits P, Thien T. Characterization of ATP-induced vasodilation in the human forearm vascular bed. Circulation. 1994;90:1891–1898.
We appreciate the comments of Rongen and colleagues and agree that comparing equimolar doses of ATP and adenosine would be a precise way of assessing the relative pharmacological efficacy of the 2 agents. In our study, we compared dosages of ATP and adenosine in micrograms per milliliter (μg/mL), which is the way that clinicians in the catheterization laboratory will understand and refer to the concentrations of these agents.R1 R2
Rongen et al are also completely correct in pointing out that we did not achieve maximal hyperemia at the 100-μg intracoronary injections of either ATP or adenosine; indeed, this was a major point of the study. As these investigators suggest, further dose escalation would probably have resulted in greater vasodilation in this experimental model. There would have been no clinical relevance to pursuing these higher doses, however, given the danger of significant side effects (particularly conduction and rhythm disturbances). The current recommended dose of intracoronary adenosine is 12 to 18 μg per injection; doses up to 40 μg can probably be given with careful monitoring. Thus, our statement that “maximal hyperemia was not achieved by either pharmacological stimulus” holds true in the dose range that is clinically applicable.
The fundamental point to emphasize here is that the thresholds that have been established from clinical studies for abnormal coronary flow reserve and fractional flow reserve were derived using the dose ranges mentioned above—the clinically tolerated doses. These thresholds were clearly not obtained under conditions of maximal hyperemia, such as would occur with ischemia or more potent pharmacological vasodilation. The clinically relevant question is how accurate and reproducible these thresholds are, given the fact that true maximal hyperemia cannot be achieved safely with the current agents.