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LETTERS TO THE EDITOR
1Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; and 2Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia
REPLY: The letter from Welsh and colleagues (6) raises many points, but we will respond here only to the major issues. We find it scientifically unacceptable to simply deny our citations reporting identification of ion channels in cultured cells. Do the correspondents wish to deny the existence of all molecules that were discovered in cultured vascular smooth muscle and endothelium? Welsh and colleagues (6) are also correct that there is no direct confirmation of the T-type channels in endothelium but that is simply because the antibodies available were very poor. We note, however, that new antibodies have been reported which confirm the expression of T-type channels in the endothelium (1).
We presented data in our article (3) indicating that hyperpolarization of the vascular smooth muscle is only one of the mechanisms that might lead to relaxation; nitric oxide, as well as other Ca2+-dependent paracrine factors, are likely involved. Thus the assertion that smooth muscle hyperpolarization "mirrors endothelial hyperpolarization" is premature. Although there may be patent connexins at the myoendothelial junction, this in no way demands that the two cells be isopotential. The relative membrane potentials of the two cells will be set by a complex interplay between ion fluxes through membrane ion channels in the individual cells, on the one hand, and the conductance of the gap junctions in the myoendothelial junction on the other hand. Thus the correspondents' inappropriate use of the word "twinning" in relation to membrane potential in the two cells goes well beyond what is already known and has been observed (2, 4, 5).
The correspondents are correct in identifying the need for measurements of Ca2+ and voltage. However, we note that such measurements would have to be made simultaneously in smooth muscle and endothelial cells and, ultimately, on intact arterioles. Such measurements simply cannot be made with existing technology in vivo. We therefore chose to measure an appropriate surrogate of the aggregate of the complex signals, the vasomotor response.
It is at best cavalier for Welsh and colleagues (6) to assert that "this study does not progress beyond the speculative nature of the title." For anyone with a deep interest in the problem, the study presents a series of careful measurements that were designed to test a complex hypothesis. As we stated clearly in our article, we certainly recognize the truth of the statements by Welsh and colleagues (6) that our work does not directly address the operation of particular ion channels and that "direct measurement of core parameters" will be required to confirm or refute our hypothesis. Unfortunately, as a practical matter, at this time, ion channels in the two cells are often accessible only in physiologically aberrant experimental circumstances.
Our results are provocative, and they are there for confirmation or refutation as new methods and new data become available. Accordingly, they should not be simply dismissed. Science cannot move forward only by minute steps that add trivial increments to our knowledge. Measurements must be guided by sometimes bold hypotheses that can be modified as appropriate methods develop and new data become available. We too found that the "conclusion is disquieting," but new ideas often are somewhat disquieting and hopefully in this case will encourage a reevaluation of some ideas of the basis for the conducted vasomotor response.
FOOTNOTES
Address for reprint requests and other correspondence: B. R. Duling, Univ. of Virginia, PO BOX 800736, Charlottesville, VA, 22908-0736 (e-mail: brd{at}virginia.edu)
REFERENCES
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