We appreciate the letter by Seifert (Seifert, 2016) regarding our recent article in the Journal of Pharmacology and Experimental Therapeutics (Bravo et al., 2016) but do not agree with its content and, moreover, believe that the arguments raised, although partially valid, actually miss the point of our study. We found that vidarabine (AraA) reduced infarct size, even when administered after coronary artery reperfusion, making this drug potentially clinically important, since most drugs must be administered before coronary occlusion in order to be effective. The take-home message in our paper is as we stated, “Regardless of whether or not AraA is a 100% pure AC5 inhibitor, this does not detract from its remarkable ability to reduce infarct size and coronary hyperemia, when administered after CAR”. Therefore, although it is of purely scientific interest to know the extent to which this drug inhibits adenylyl cyclase (AC)5 versus AC6, it is irrelevant to its ultimate utility clinically, if the drug can be made safer.
We also noted in our article that there is controversy about whether AraA is a pure AC5 inhibitor. However, we also pointed out that AraA reduced adenyl cyclase activity significantly in AC5 transgenic mice, but not at all in AC5 knockout mice, and it exerted little effect in either wild-type or AC6-transgenic mice. Therefore, it appears incontrovertible that AraA does have an action reducing AC5. We also argued that if the mechanism of AraA was much different from an AC5 inhibitor, the addition of this drug to an AC5 knockout animal would induce even greater infarct protection owing to its different mechanism. We did not observe this. Infarct size was reduced further by only 10% with the addition of AraA. As Seifert points out, these data could become statistically significant with a greater number of animals studied. This is correct; we calculate we would need 16 animals in each group to reach statistical significance, but we would still be faced with the more important issue: there is only a 10% difference.
Finally, the argument by Seifert that AraA also has AC6 inhibitory activity may be correct but is misleading. To address this point we performed additional experiments in AC6 knockout mice with three mice receiving AraA after reperfusion and four mice receiving vehicle. In contrast to the results in the AC5 knockout mice, AraA significantly reduced infarct size further in the AC6 knockout mice, with similar areas at risk (see Fig. 1). Furthermore, deletion of AC6 in the AC6 knockout actually has been reported to have adverse effects on cardiac function (Tang et al., 2008, 2013). Hammond and coworkers have always argued that overexpressing, not reducing, AC6 is beneficial to the heart (Roth et al., 1999; Lai et al., 2004; Takahashi et al., 2006; Lai et al., 2008; Sugano et al., 2011). In contrast, the AC5 knockout extends longevity by one-third (Yan et al., 2007), protects against cancer (De Lorenzo et al., 2014), and protects the heart against pressure overload (Okumura et al., 2003), catecholamine cardiomyopathy (Okumura et al., 2007), and myocardial ischemia (Iwatsubo et al., 2012). Moreover, it protects against diabetes and reduces weight, despite increased food intake (Ho et al., 2015), and improves exercise performance (Vatner et al., 2015). Accordingly, to put this message into perspective, if the next generation AraA was designed for oral administration and without toxicity, and it prolongs lifespan, protects against heart disease and cancer, increases exercise capacity, and allows you to eat more but reduce your weight and blood levels of cholesterol and triglycerides, would you take this pill?
Wrote or contributed to the writing of the manuscript: Bravo, D. Vatner, S. Vatner.
- Received April 27, 2016.
- Accepted May 25, 2016.
This Letter to the Editor is in response to
“Does Vidarabine Mediate Cardioprotection via Inhibition of AC5?” by Seifert, found in J Pharmacol Exp Ther 2016, 358:242–243.
- adenylyl cyclase
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics