Journal of Applied Physiology
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J Appl Physiol 102: 2075, 2007; doi:10.1152/japplphysiol.01258b.2006
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POINT-COUNTERPOINT

REBUTTAL FROM DR. ROBERTSON

Two words came to mind as I read my opponent's side of the argument: "smoke" and "mirrors." To quote my esteemed opponents: "our strongest argument comes from the freshly isolated PASMC model." While I do not regard these experiments as "ugly," they may have more than a few unsightly blemishes! The observation that enzymatically dispersed PASMCs constrict to hypoxia in no way negates a primary role for an endothelium-dependent Ca2+ sensitization in the intact artery or in the whole animal. To infer that the PASMC is the sole repository for the mechanism(s) of HPV as it can constrict to hypoxia, with complete disregard to the myriad of cellular changes that likely occur during its rather traumatic isolation, is one inference too far!

I must also take issue with my opponent's argument that HPV "cannot be explained by a mechanism involved in the vasoconstriction to prostanoids or phenylephrine." I must admit to finding this argument rather baffling. Could not the specificity, with respect to HPV, be attributed to an endothelium-derived constrictor factor released locally within the lung, and/or one that acts solely within the pulmonary circulation rather than in the signal transduction pathway it activates?

It is interesting that my opponents state that "methodological differences can be debated in the isolated PA model." Indeed they can and since my opponents state that "in our hands, rat resistance PAs can have full HPV" (1), this seems like a suitable point to debate some methodological differences! In their work, the PAs were ~74 µm in diameter and had a resting tension of 700 mg (~6.9 mN). With a generous allowance of between 1 and 2 mm vessel length, for an artery of this diameter, the equivalent transmural pressure would probably lie between ~500 and ~1,000 mmHg compared with 15–30 mmHg reported from other laboratories (2–9). Moreover, the resultant constrictor responses in this report were, perhaps unsurprisingly, given the "resting" conditions, rather small (~100 mg or ~1 mN) compared with those reported by other investigators using small PAs (~30 mN; Refs. 2, 4, 6, 7). In the laboratories in which I have had the privilege to work, a pulmonary artery with a resting tension of 7 mN and a subsequent constrictor response of 1 mN would have been a candidate for life support measures!

Finally, HPV (like a Ferrari) is multifactorial. It requires a spark (the mitochondria and increases in cytosolic Ca2+), fuel (glucose for glycolysis), and an accelerator (Rho kinase). But one thing is missing in this Ferrari...oh yes, the driver—something to put the pedal to the metal when it's really needed. ...now I wonder what that could be?

REFERENCES

  1. Archer SL, Wu XC, Thebaud B, Nsair A, Bonnet S, Tyrrell B, McMurtry MS, Hashimoto K, Harry G, Michelakis ED. Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells. Circ Res 95: 308–318, 2004.[Abstract/Free Full Text]
  2. Dipp M, Evans AM. Cyclic ADP-ribose is the primary trigger for hypoxic pulmonary vasoconstriction in the rat lung in situ. Circ Res 89: 77–83, 2001.[Abstract/Free Full Text]
  3. Jones RD, Morice AH. The effect of the nitric oxide synthase inhibitor Ngamma-nitro-L-argine methyl ester on hypoxic pulmonary vasoconstriction. Eur J Pharmacol 402: 111–117, 2000.[CrossRef][ISI][Medline]
  4. Leach RM, Hill HM, Snetkov VA, Robertson TP, Ward JPT. Divergent roles of glycolysis and the mitochondrial electron transport chain in hypoxic pulmonary vasoconstriction of the rat: identity of the hypoxic sensor. J Physiol 536: 211–224, 2001.[Abstract/Free Full Text]
  5. Morecroft I, Loughlin L, Nilsen M, Colston J, Dempsie Y, Sheward J, Harmar A, MacLean MR. Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 313: 539–548, 2005.[Abstract/Free Full Text]
  6. Robertson TP, Aaronson PI, Ward JP. Hypoxic vasoconstriction and intracellular Ca2+ in pulmonary arteries: evidence for PKC-independent Ca2+ sensitization. Am J Physiol Heart Circ Physiol 268: H301–H307, 1995.[Abstract/Free Full Text]
  7. Robertson TP, Dipp M, Ward JP, Aaronson PI, Evans AM. Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat. Brit J Pharmacol 131: 5–9, 2000.[CrossRef][ISI][Medline]
  8. Teng GQ, Barer GR. In vitro responses of lung arteries to acute hypoxia after NO synthase blockade or chronic hypoxia. J Appl Physiol 79: 763–770, 1995.[Abstract/Free Full Text]
  9. Thomas BJ, Wanstall JC. Alterations in pulmonary vascular function in rats exposed to intermittent hypoxia. Eur J Pharmacol 477: 153–161, 2003.[CrossRef][ISI][Medline]




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