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EDITORIAL FOCUS
Dimera Incorporated, Portland, Oregon
WHETHER AN ION CHANNEL ELEMENT could explain vasomotor responses that must inherently be coordinated among thousands of cells that comprise the blood vessels supplying end organs has been one of the deep puzzles in circulatory physiology for decades. In the recent article by Figueroa et al. (4), it is formulated into an ingenious presentation of microcirculatory function that promises to open a productive path to discoveries.
For decades, medical science has been frozen in progress on the problem of longitudinal conduction of vasomotor responses, which could have chemical, ionic, electrical, or even mechanical mechanisms. An answer to this question demands, at the very least, the pursuit of multidisciplinary talents. Advanced concepts of microcirculatory function, electrophysiology, biophysics, cell biology, pharmacology, and ion channel scientific investigation are simultaneously required in a dynamic interaction to navigate the challenges of successful advancement of understanding of cardiovascular function.
The deductions supported by the data lead to a model of electrical propagation of vasodilation over a distance capable of coordinating the well-known increases in blood flow that occur during circulatory dynamics. This is a seminal accomplishment, inasmuch as the inherent biophysical parameters do not resemble those of nerve, skeletal muscle, and heart. Indeed, the pioneering characterization by Hugh Davson (3) of electrochemical signals in single cells is, after half a decade, being expanded. At a time when electrophysiologists were most attracted to study of fast conduction by voltage-gated ion channels, those studying microcirculation were analyzing the orders-of-magnitude slower and smaller electrical events that formed one logical (but improbable) option to explain propagated dilator events that were undeniable in the microcirculation of the hamster cheek pouch and cremaster muscles, the bat wing, and other vivid microcirculatory displays.
Dilations that occur over >10 s and propagate along small, thin-walled vessels at velocities thousands of times slower than myelinated nerve seemed unlikely to be explicable by the Hodgkin-Huxley-Cole-Katz membrane excitation mechanism, which dominated thinking and pioneered acceptance of the profound voltage-clamp approach. Kenneth Cole's seminal book (2) on the relationship between electricity and life focused on fast-conduction (1 m/s) nerve mechanisms, applied the physics of the trans-Atlantic cable to the single cell, and appeared at about the time his seminar, providing a serendipitous vivid and thorough first encounter with the concepts and highly mathematical approaches integral to their predictive analysis, was presented to the Physiology Department at the University of Virginia. The remarkable insights of Hodgkin and Huxley (9, 10) building on Bernard Katz's (11) breakthrough synopsis of the membrane basis for rapid conduction of nerve excitation over distances of 500–1,000 mm solved profound interdisciplinary problems and led to decades of productive research on membrane excitability that continue to lead the advancement of quantitative biology. Application of rigorous mathematical cable concepts to the cardiovascular system by those of us in the laboratory of Silvio Weidmann in Bern, Switzerland, in 1977 to test for enhancement of conduction by physiological concentrations of angiotensin succeeded in discovery of cardiac muscle enhancement (5) but was not definitive in studies of modulation of conduction in small blood vessels, because they were perturbed by the dissection. The need for an intact circulation is a formidable complication requiring an approach such as that used by Figueroa et al. (4).
Although the T-type calcium channels and sodium channels in vascular muscle were reported first in 1986 (1, 16), years elapsed before a pharmacological approach was possible (12). Further regulation of blood vessels via receptors and, perhaps, even ion channels under the epigenetic control of steroid hormones (8, 13) may emerge as a further implication. Evidence that altered modulation of calcium and other ion channels may contribute to hypertension also remains a viable hypothesis (15). Explanations of conducted constrictor and dilator phenomena in the intact circulation have remained an enigma (6) since the considerable problems of conduction mechanisms in smooth muscle physiology were explicitly delineated (14).
In this issue of American Journal of Physiology-Heart and Circulatory Physiology, the insight of Figueroa et al. (4) is the recognition of the primacy of sodium channels and Cav3.2 channels in the endothelial cell membrane for conduction of vasodilation. Beyond the coupled actions of transient calcium and sodium channel currents, the mechanistic model introduced by Figueroa et al. (Fig. 10 in Ref. 4) recognizes the influx of calcium as the sustaining factor for dilation in the endothelial cells as well, with the corollary that dilation mechanisms, notably via activation of endothelial nitric oxide synthase and endothelium-derived relaxing factor, can be activated in a conduction network. Long-lasting (
10 s) endothelial hyperpolarizations, which occur with potassium channel activation, make plausible the time course required. Intracellular binding and transport rates to restore the calcium balance at specific intracellular endothelial sites are consistent with this new world (of slow and prolonged) conduction phenomena. The evidence presented by Figueroa et al. convincingly establishes that endothelial integrity is necessary for propagation of the conducted vascular response, strongly buttressing the endothelial conduction hypothesis. Use of bupivacaine to more thoroughly (than tetrodotoxin alone) test the sodium channel hypothesis is another elegant feature of the experimental design. The data suggest involvement of specific isoforms of the Nav channel in endothelium-dependent signal propagation. Support for the role of the sodium channel in the conducted vasodilation hypothesis with a strong array of immunocytochemical and polymerase chain reaction data form a compelling array. Use of BAPTA to separate the vasodilator response from the conduction provides convincing data that the conduction mechanism can be explained by ion channels.
Block of the T-type calcium channels with mibefradil uniquely eliminated the conducted vasodilation, coincident with a maximal dilation response. Other T-channel blockers (nickel and amiloride) were less effective in suppressing vasodilator conduction, but interaction of both sodium and T-type calcium channels in the endothelium may have a significant role in coordination of vasoconstriction and vasodilation. Block of T-type calcium channels with sufficient selectivity to offer unique therapeutic advancement has demonstrated the logic of pursuing ion channel specificity (7). Only a few years ago, calcium and sodium channels were often said to be undiscovered and, possibly, absent in vascular endothelial cells; therefore, the identification of sodium and calcium channel depolarizing influences in key roles represents a major advance.
Conducted vasodilation in the vasculature over thousands of micrometers and dependent on sodium and calcium channels in an intact endothelium presents a major insight that will inevitably lead to recognition of important ion channel mechanisms. Such mechanisms promise to lead to significant advances in better understanding of physiology and pathophysiology in the organ system that is perhaps least understood, inasmuch as cardiovascular disease is the undisputed leading cause of death around the world. Magnificent basic science as presented by Figueroa et al. (4) will undoubtedly provide useful new concepts and advance therapeutic success. As the authors aptly conclude, their article opens a new universe of questions that merit extensive exploration, for which they have provided an exemplary report of discovery and achievement.
FOOTNOTES
Address for reprint requests and other correspondence: R. K. Hermsmeyer, Dimera, Inc., 2525 NW Lovejoy, Suite 311, Portland, OR 97210 (e-mail: rkh{at}dimera.net)
REFERENCES
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