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POINT-COUNTERPOINT
Hamlet
When serious scientists consistently report different findings it is likely that the disparity lies in the conditions of the experiments. Two thoughts: first, for the oxygen-sensitive, resistance pulmonary arteries, physiological hypoxia lies between 40 and 80 mmHg and HPV starts within seconds as PO2 falls below 80 mmHg. A PO2 <40 mmHg may be hypoxia in systemic vessels but threatens survival if present throughout the lungs. Second, cultured cells do not behave as freshly dispersed cells. For instance, there is a marked difference in function and expression of Kv channels, in sodium current, and in membrane potential between cultured and dispersed smooth muscle cells (6). One should not assume that cultured cells will react as they would in life. Observations cited by our opponent in cultured PASMCs using PO2 of 12 mmHg may not help (8). Similarly, cited reports of ROS increasing after 5–10 min at 25 mmHg in PASMCs after multiple passages are outside the relevant criteria (3). Another cited paper (4) describes EPR spin adduct spectra after 60 min of hypoxia but concludes, "neither lucigenin-derived chemiluminescence nor EPR spectroscopy provided decisive evidence that hypoxia increased ROS generation in distal pulmonary arteries." The work of Weissmann et al. is quoted four times, but the reader should review the data to discern the facts. In the rat lung with increasing severity of hypoxia, the smallest measured ROS and superoxide production correlates with almost the greatest HPV (Fig. 3 of Ref. 9) Similarly, in the wild-type mouse lung, ROS and superoxide decrease with hypoxia, (Fig. 9 of Ref.10). We endorse the choice of these references.
We are gratified that our honorable opponent concedes that, "most agree that mitochondria function as the oxygen sensor for HPV," as we have advocated for 20 years that a redox change related to mitochondrial function is the sensor, signaling to K+ channels to initiate HPV (1, 2). However, not all mitochondria are created equal and those from PASMCs are more depolarized and make more ROS at a given PO2 than those from systemic arterial SMC (5). Moreover, only PASMC mitochondria make fewer ROS in response to physiological hypoxia. The first half of our opponent's treatise seeks to find a theoretical reason for the proposed paradoxical increase in ROS during hypoxia. He quotes the authoritative paper by J. F. Turrens (7). However, Dr. Turrens writes, "The proposed increase in ROS formation during hypoxia is difficult to explain." We agree. ROS down in HPV; yes. ROS, irrelevant; possibly. ROS up; no way!
REFERENCES
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