Inasmuch as ADM is widely dispersed in various tissues, and particularly in vascular endothelium, Zhang et al. (21) propose that ADM may be a contributor to the pathophysiology of POTS. This aspect of the study is interesting and may open doors for further assessment of the role of vasoactive peptides in this condition. On the other hand, the observation that the POTS patients with the highest ADM levels responded best to the vasoconstrictor prodrug midodrine is more difficult to understand for several reasons. First, although it is possible that the handling of midodrine is different in Chinese children than in young persons in Western countries, the vast extant reported experience in the adolescent and young adult age groups does not tend to indicate that midodrine at modest doses (even in combination with salt and volume for that matter) is predictably effective for treating POTS. Second, in the current report by Zhang et al. (21), reliance for success is placed on symptom score improvement, whereas physiological measures such as heart rate changes with upright posture (their Table 4) were not substantially different between midodrine responders and nonresponders (Δ heart rate post-treatment: 32.6 ± 14.8 beats/min vs. 32.2 ± 10.4 beats/min, respectively) despite the p values. Thus, it is difficult to ascribe any benefit to cardiovascular physiological/pharmacological effects of midodrine. Third, the midodrine dose prescribed was very low (2.5 mg/day) and does not seem to have been administered either in divided doses as its pharmacology would dictate (23), or based on weight, as is common practice in pediatrics. In this regard, midodrine is a prodrug that is well absorbed, but its effect is delivered after conversion by hydrolytic cleavage to deglymidodrine. The latter has a somewhat longer half-life than midodrine (2 to 3 h vs. 0.5 h) with a maximum effect at 1 h and a duration of action of 4 to 6 h (23). Even allowing for some variability that may be found in dysautonomia patients and potential pharmacogenetic differences related to the Chinese patient population, it is difficult to conceive that the pharmacological effect could be long enough to be effective with once-daily dosing. Finally, based on their midodrine observations, Zhang et al. (21) suggest that the high ADM patients are the ones whose principal POTS pathophysiology is vascular dilation (i.e., the redistributive form), as opposed to the less common hyperadrenergic form, and thus would be the subset best treated with vasoconstrictor agents. This pathophysiological concept seems plausible. As noted earlier, the natriuretic peptides including ADM are known to be vascular relaxants and to reduce circulating volume by several mechanisms, including fluid transfer through vessel walls to the interstitium, diuresis, and redistribution, especially to the splanchnic bed (18,20). The latter is particularly large potential circulating volume “sink,” which is known to respond to nitric oxide in a manner that could fit one of the ADM modes of action. In combination then, increased ADM could account for the POTS clinical combination of orthostatic intolerance and increased vascular permeability with peripheral edema. Further, a net reduction of circulating volume may lead to decreased heart size and the need for more rapid heart rates to accommodate to posture and exercise (i.e., the tachycardia component of POTS) (24). However, with all this having been said, one might have expected that the utility of any therapeutic vasoconstrictor agent would be more challenged, rather than less, in the presence of high levels of ADM; in other words, one might have predicted just the opposite effect than that reported in this issue of the Journal by Zhang et al. (21).