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EDITORIAL FOCUS
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
CONTROVERSY CONTINUES regarding the cellular mechanisms of hypoxic vasodilation. The vascular endothelium may contribute to hypoxic dilations by releasing relaxing factors that act on the smooth muscle (4, 6–8). In contrast, numerous studies have suggested a role of the vascular smooth muscle as a primary site for sensing decreased oxygen tension independent of metabolic factors released from the endothelium or surrounding tissues (1, 5, 8, 10). Two major paradigms for vascular smooth muscle relaxation associated with hypoxia include 1) activation of plasma membrane ATP-sensitive K+ (KATP) channels and 2) decreased voltage-sensitive Ca2+ influx. However, these paradigms may not be mutually exclusive, and interactions between them are highly probable. Specifically, K+ efflux through activated KATP currents and the resulting membrane hyperpolarization could decrease voltage-sensitive Ca2+ influx (8). Other intracellular components may also contribute to hypoxic relaxations, including decreases in intracellular pH and elevations of inorganic phosphate (11).
Considering the above paradigms, requirements for the examination of smooth muscle hypoxic dilation/relaxation require 1) demonstration of hypoxic relaxations independent of the endothelium and external metabolic factors and 2) demonstration of hypoxia-induced smooth muscle KATP channel activation/hyperpolarization or hypoxia-induced decrease of voltage-sensitive calcium current using electrophysiological (patch-clamp) techniques. For analysis of ATP-sensitive currents altered by hypoxia, voltage-clamped cells must maintain metabolic activity, and pipette solutions should not dialyze the cell or alter intracellular constituents, in particular the concentrations of ATP and ADP. For this purpose, a useful approach is the amphotericin B-perforated patch technique (1, 5).
In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Quayle and colleagues (9) report a series of well-designed experiments examining the role of smooth muscle KATP channels and voltage-sensitive calcium influx in hypoxic relaxations of rat femoral arteries. Isolated rat femoral arterial segments preconstricted with phenylephrine showed reversible hypoxia-related relaxations, which were not altered by the KATP channel inhibitor glibenclamide or endothelial cell removal. Hypoxic relaxations also occurred in arteries contracted with high K+ (80 mM). This clearly eliminated a role of smooth muscle KATP channels and K+ efflux in the observed relaxations. Results were substantiated in their electrophysiological evaluations. Hypoxia did not increase KATP current of voltage-clamped, amphotericin B-perforated cells. However, it should be noted that the electrophysiology was performed on cells maintained at room temperature with 10-min hypoxic recordings. Under these conditions, inhibition of glycolytic or mitochondrial ATP production with 2-deoxyglucose and oligomycin B also did not activate KATP currents. In contrast, the mitochondrial protonophore carbonyl cyanide m-chlorophenylhydrazone activated KATP current, which was enhanced by the dual application of 2-deoxyglucose. KATP current was also activated by the oxygen quenching compound dithionite. Alternatively, in cells dialyzed with ATP, hypoxia reversibly inhibited voltage-activated Ca2+ currents and decreased depolarization-induced Ca2+ influx. Taken together, this study provides compelling evidence that in rat femoral arterial smooth muscle, hypoxia causes relaxation through mechanisms that decrease voltage-dependent Ca2+ influx independent of KATP channel activation. Furthermore, KATP currents may remain stable during hypoxia because ATP concentrations are not lowered to levels required for KATP channel activation.
These results are in agreement with previous findings using isolated hamster cremaster arteriole smooth muscle in which hypoxia did not alter conductance or membrane potential of voltage-clamped amphotericin B-perforated cells (5). However, hypoxic reduction of norepinephrine contractions were inhibited by glibenclamide and 35 mM K+. Similarly, in endothelium-denuded porcine coronary arterial rings, hypoxic relaxations were resistant to glibenclamide and high K+ (10). In isolated human coronary smooth muscle cells, low oxygen tension decreased L-type calcium current and reduced cytosolic Ca2+ (10). A role of decreased voltage-sensitive Ca2+ influx during hypoxia has also been demonstrated in the smooth muscle from porcine coronary, rabbit cerebral, celiac, and femoral arteries and hamster cheek pouch arterioles (2, 3, 10, 13).
In contrast, hypoxia activated glibenclamide-sensitive K+ currents in amphotericin B-perforated cells of isolated porcine coronary smooth muscle cells (1). However, caution should be considered when comparing KATP-dependent hypoxic responses between different arterial preparations. As reviewed by Weintraub (12), gene product composition of the inwardly rectifying potassium channel and sulfonylurea receptor subunits and further posttranslational modification results in variations of the KATP channel structure. These variations can possibly modify responses to intracellular nucleotide concentrations and other metabolic factors.
As reviewed by Taggart and Wray, "there are many potential regulatory sites of the excitation-contraction coupling in smooth muscle during conditions of altered metabolism" (11), suggesting that altered forces during hypoxia probably result from the combination of factors. Furthermore, in the vasculature, these factors may vary with species and vascular bed. Whereas the mechanisms of hypoxic vasorelaxation are complex, results from the current study by Quayle et al., (9) support the role of decreased voltage-sensitive Ca2+ influx as a primary mediator of the hypoxic response. As with this study, future evaluations of the role of voltage-dependent Ca2+ influx and KATP channels in hypoxic vasorelaxation will require an integrated approach with pharmacological and/or electrophysiological isolation of the specific mechanisms in question.
ACKNOWLEDGMENTS
I thank Dr. S. L. Pfister for reviewing this document.
FOOTNOTES
Address for reprint requests and other correspondence: K. M. Gauthier, Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: kgauth{at}mcw.edu)
REFERENCES
This article has been cited by other articles:
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  G. Zhao, A. Adebiyi, Q. Xi, and J. H. Jaggar Hypoxia reduces KCa channel activity by inducing Ca2+ spark uncoupling in cerebral artery smooth muscle cells Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2122 - C2128. [Abstract] [Full Text] [PDF]
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