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POINT-COUNTERPOINT
Understandably, the thrust of their article concerns the case for the Redox hypothesis, the central tenet of which is that the primary response to hypoxia is a fall in ROS and subsequent reduction and inhibition of KV channels. However, it has been suggested that the depolarization associated with HPV may actually be secondary to activation of non-selective cation channels (NSCC) by, for example, store release, as NSCC blockers and ryanodine essentially abolish HPV, whereas L-type blockers are generally less effective (1, 9). Apart from K+ channels, all other components of the "executive" of HPV are known to be activated by increased ROS, e.g., ryanodine channels, NSCCs, and upstream activators of SOC, ROC, and Rho kinase such as Src (e.g., Refs. 6–8).
The lack of vasoconstriction during hyperoxia is not absolutely surprising, as hyperoxia may preferentially promote NAD(P)H oxidase ROS production (4), primarily extracellular and possibly prorelaxant, and other O2-dependent mechanisms such as NO synthase. The real estate cry of "location, location!" is of pre-eminent importance; certainly the close approximation of peripheral mitochondria with SR and sarcolemma is optimal for intracellular hypoxic/ROS/Ca2+ signaling (7). Use of novel, organelle-targeted ROS probes may well elucidate these aspects. Similar reservations can be applied to the use of powerful and promiscuous oxidizing and reducing agents such as DTNB and dithiotheitol—these may well affect K+ channels, but do they mimic physiology or industry?
The very recent study concerning mitochondrial defects in Fawn-Hooded rats (2) is intriguing, but could possibly be interpreted otherwise; such mitochondrial damage is reminiscent of Ca2+ overload, which can actually increase mitochondrial ROS production. Indeed, notwithstanding the reported measurements of ROS, and directly contradicting this paper, numerous reports have shown that HIF is activated by increased ROS (e.g., Refs. 3, 6).
Finally, our chums try to hoist us with our own petard with a quote from the introduction to our recent review. Tut tut. The quote is truncated, since it is followed by the all important word "However ...", which leads to the meat of the review (1).
REFERENCES
-Kv channel pathway disrupts oxygen-sensing and triggers pulmonary arterial hypertension (PAH) in fawn-hooded rats: similarities to human PAH. Circulation. In press.
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