HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (31) Citing Articles via Google Scholar Google Scholar Articles by Hecker, M. Search for Related Content PubMed PubMed Citation Articles by Hecker, M.

Endothelium-Derived Hyperpolarizing Factor—Fact or Fiction?

Markus Hecker

M. Hecker is a professor in and Director of the Department of Cardiovascular Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany.

	Abstract

 
The vascular endothelium releases a diffusible factor that hyperpolarizes and hence relaxes vascular smooth muscle cells predominantly through activation of Ca²⁺-dependent K⁺ channels. In the coronary circulation, this endothelium-derived hyperpolarizing factor appears to be a cytochrome P₄₅₀-derived arachidonic acid epoxide, the release of which may play a crucial role in the maintenance of coronary blood flow in arteriosclerosis.

	Introduction

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
The endothelium plays a major role in vascular homeostasis by releasing vasoactive autacoids such as nitric oxide (NO) and prostacyclin (PGI₂). The basal synthesis of these autacoids is greatly enhanced in the presence of receptor-dependent agonists such as acetylcholine or bradykinin as well as by receptor-independent stimuli such as hypoxia, an increase in shear stress, or cell deformation. Apart from the shear stress-induced release of NO, which is largely Ca²⁺-independent, an increase in the intracellular concentration of Ca²⁺ is the common denominator for endothelial autacoid production, since both phospholipase A₂ (the rate-limiting enzyme for PGI₂ synthesis) and NO synthase are Ca²⁺-dependent enzymes (Fig. 1).

View larger version (31K): [in this window] [in a new window]   FIGURE 1. Schematic view of pathways leading to nitric oxide (NO) and prostacyclin (PGI2) formation in endothelial cells and their effects on smooth muscle cell tone. KCa, KATP, and Kdr, Ca2+-dependent, ATP-dependent, and delayed-rectifier K+ channels, respectively; 20:4, arachidonic acid; ACh, acetylcholine; Bk, bradykinin; COX, cyclooxygenase; NOS, NO synthase; PCS, prostacyclin synthase; PL, phospholipid; PLA2, phospholipase A2; L-Arg, L-arginine.

	Discovery of an endothelium-derived hyperpolarizing factor

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

Recently, however, a major debate has evolved concerning the identity and existence of this relaxing principle, so that some researchers now tend to refer to EDHF as the "eternally deceptive relaxing factor." Several experimental problems seem to have spurred this debate, one of which is that endothelium-dependent hyperpolarization has frequently been studied without combined cyclooxygenase and NO synthase blockade. The observed changes in membrane potential, therefore, could have resulted not only from the action of EDHF but also from that of NO or PGI₂, both of which also fulfill the criteria of an endothelium-derived hyperpolarizing factor (3, 5, 10).

Thus NO is capable of activating Ca²⁺-dependent K⁺ channels (K_Ca channels) directly, and both K_Ca channels and ATP-dependent K⁺ channels (K_ATP channels) indirectly, by increasing the intracellular concentration of cGMP. PGI₂, on the other hand, has been shown to activate smooth muscle cell K_ATP channels through the secondary rise in cAMP after binding to the corresponding cell surface receptor. Moreover, both autacoids are capable of activating delayed-rectifier K⁺ channels (K_dr channels) in vascular smooth muscle cells (Fig. 1) by elevating the intracellular concentration of cAMP (8). The latter effect and that of NO on K_ATP channel activity is presumably brought about by preventing the breakdown of cAMP through the cGMP-inhibitable phosphodiesterase III.

Other equally important methodological problems relate to the difficulty of assaying the release of a diffusible factor from the endothelium and the use of some nonspecific pharmacological tools to elucidate both the identity and mechanism of action of EDHF (see below).

	Mechanism of action

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
In most vascular beds studied thus far, the NO/PGI₂-independent portion of the relaxant response to a receptor-dependent agonist is inhibited by K_Ca channel inhibitors such as apamin, charybdotoxin, and tetrabutylammonium but not by the K_ATP channel blocker glibenclamide (1, 3, 5, 8, 10, 13, 14). Results with the K_dr inhibitor 4-aminopyridine tend to vary, but the majority of findings suggest that the agonist-induced EDHF-mediated relaxation is not mediated by activation of K_dr channels (8). Together, these data support the concept that the hyperpolarization and hence the relaxation elicited by EDHF is mediated by the opening of K_Ca channels in vascular smooth muscle cells, albeit with varying conductance depending on the vascular bed studied (Fig. 2).

View larger version (26K): [in this window] [in a new window]   FIGURE 2. Schematic view of pathway leading to EDHF formation in endothelial cells and their effects on smooth muscle cell tone. EOX, epoxygenase.

	Characterization of EDHF as a diffusible factor

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

By using a novel bioassay system in which the luminal effluate of endothelium-intact bovine or porcine coronary artery segments superfuses cultured vascular smooth muscle cells, the membrane potential of which is monitored by the patch-clamp technique, two groups have recently demonstrated independently from each other that a diffusible factor, pharmacologically distinct from NO and PGI₂, is released from the endothelium of these arteries in response to bradykinin (6, 12). This factor hyperpolarized the detector cells by activating K_Ca channels with a single-channel conductance of 250 pS (so-called maxi K⁺ or BK_Ca channels), and this effect was blocked both by the highly selective BK_Ca channel inhibitor iberiotoxin and the broad-range K_Ca channel inhibitor tetrabutylammonium (6, 11, 12). Moreover, as K_Ca channel open probability increased in the cell-attached configuration, it would appear that EDHF activates these channels indirectly, possibly involving membrane-associated second messenger pathways (6, 12).

	Epoxyeicosatrienoic acids

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
Although the exact chemical identity of EDHF has not yet been elucidated, a number of studies suggest that, at least in coronary arteries from many species (including human coronary arteries) and possibly also in the renal, carotid, and mesenteric arteries, a cytochrome P₄₅₀-derived metabolite of arachidonic acid is released after stimulation with bradykinin or acetylcholine. These observations are consistent with early reports of an increased arachidonic acid and acetylcholine-induced relaxation in these blood vessels after induction of cytochrome P₄₅₀ monoxygenases (1, 11).

There is actually a rather broad consensus that EDHF in these and other vascular preparations is an arachidonic acid metabolite or a closely related molecule. More problematic seems to be the acceptance of the term cytochrome P₄₅₀-derived arachidonic acid metabolite. The primary reason for doubting this hypothesis is that common cytochrome P₄₅₀ inhibitors, such as clotrimazole or proadifen (SKF-525a), which effectively suppress EDHF-mediated relaxant responses, at higher concentrations also significantly impair the agonist-induced increase in intracellular Ca²⁺ in endothelial cells. Moreover, they have been shown to interfere with the activation of K_ATP channels and possibly also that of K_Ca channels in vascular smooth muscle cells (3, 5, 10). Inhibitors that are more selective for the cytochrome P₄₅₀-dependent oxygenation of arachidonic acid, such as 17-octadecynoic acid (17-ODYA), on the other hand, frequently cause the problem of effectively reducing the EDHF-mediated relaxation in one preparation (e.g., bovine or porcine coronary artery) but not in another (e.g., rabbit carotid or rat mesenteric artery; Refs. 1, 6, 11–13). On the basis of these pharmacological intervention trials, several reports have been published in recent years claiming that EDHF cannot be a cytochrome P₄₅₀-derived arachidonic acid metabolite in certain vascular beds. Indeed, no one at present would earnestly dispute that, in addition to the cytochrome P₄₅₀-derived arachidonic acid metabolite, other types of EDHF exist in different vascular beds (see below). However, there is also a tendency toward overlooking the possibility that many cytochrome P₄₅₀ enzymes capable of oxygenating arachidonic acid exist in different vascular beds and species that are likely to display a markedly different inhibitor profile.

What, however, is the evidence arguing for EDHF being a cytochrome P₄₅₀-derived arachidonic acid metabolite? Epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12- and 14,15-EET; Fig. 3) are produced by endothelium-intact coronary arteries (1, 6, 8, 10–13) and, when applied to endothelium-denuded coronary artery segments, are capable of producing both hyperpolarization and relaxation (1, 6, 10, 11, 13). This hyperpolarization seems to be exclusively mediated by the activation of K_Ca channels (8), in contrast to the hyperpolarizing effects of NO or PGI₂ that can be mediated by the activation of K_ATP, K_Ca, and K_dr channels (see above). Moreover, with the aid of the novel bioassay technique it was demonstrated that the bradykinin-induced release of EDHF from luminally perfused coronary arteries and cultured endothelial cells is not only sensitive to clotrimazole, 17-ODYA, and miconazole (6, 11, 12) but also significantly augmented by treatment of the segments or cells with ß-naphthoflavone, an inductor of cytochrome P₄₅₀ gene expression (11). In addition, the hyperpolarizing effect of the luminally released factor on the detector smooth muscle cells was precisely mimicked by an arachidonic acid epoxide (5,6- and 14,15-EET; Refs. 6 and 11). These epoxides, on the other hand, have been shown by various groups to activate K_Ca channels in vascular smooth muscle cells, including those from the coronary arteries in question (1, 6, 10, 11, 13). Finally, certain anesthetics that do not interfere with agonist-induced Ca²⁺ mobilization in endothelial cells or K⁺ channel activation in smooth muscle cells (e.g., thiopental) are also capable of selectively blocking the endothelium-dependent NO/PGI₂-independent vasodilatation in different vascular beds (rabbit carotid artery, rat heart, human renal artery). This effect appears to be based on the cytochrome P₄₅₀-inhibiting properties of these anesthetics as well (7, 11). Additional evidence for the critical role of a cytochrome P₄₅₀-dependent epoxygenase in bradykinin-induced NO/PGI₂-independent coronary dilatation may be derived from experiments in which expression of these enzymes (e.g., cytochrome P₄₅₀ 2C8) is downregulated by using corresponding antisense oligodeoxynucleotides.

View larger version (9K): [in this window] [in a new window]   FIGURE 3. Chemical structure of two EDHF candidates, anandamide and one isomer [11,12-epoxyeicosatrienoic acid (EET)] of a group of 4 regiospecific cytochrome P450-derived arachidonic acid epoxides.

	Anandamide

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

	Endothelium-derived K+

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
The latest contribution in the quest for the identity of EDHF is a suggestion that, in the hepatic and mesenteric arteries of the rat, acetylcholine causes an activation of endothelial K_Ca channels that are sensitive to apamin plus charybdotoxin but not iberiotoxin. The resulting K⁺ efflux through these K_Ca channels is supposed to double the concentration of K⁺ in the myoendothelial space that, through activation of both inwardly rectifying K⁺ channels (K_ir channels) and Na⁺-K⁺-ATPase, hyperpolarizes and hence relaxes the adjacent smooth muscle cells (4). Although this is undoubtedly an interesting hypothesis, it does not appear to be unequivocally supported by the data provided. Moreover, an increase in myoendothelial K⁺ of this magnitude is unlikely to be effective in thick-walled arteries such as coronary arteries (see below), so that the authors' claim of the universal validity of their hypothesis appears to be somewhat premature. Indeed, it remains to be demonstrated that this is not simply another EDHF-like principle that is restricted to this species and type of blood vessel.

Activation of Na⁺-K⁺-ATPase by a diffusible endothelium-derived factor was already proposed a decade ago for canine coronary arteries (3, 5); however, the main problem associated with this hypothesis was and still is the lack of selectivity of the Na⁺-K⁺-ATPase inhibitor ouabain. Moreover, in the experiments with rat arteries, especially in the mesenteric artery preparation, there was a clear dissociation of the effects of ouabain plus barium (which was employed as a K_ir channel inhibitor) on the response to acetylcholine: smooth muscle cell hyperpolarization was virtually abolished, whereas the agonist-induced relaxation remained largely unaffected. Furthermore, the concern prevails that by simply inserting a microelectrode into the space between the endothelium and the media—which is extremely difficult to achieve from a technical point of view—it seems impossible to distinguish between the rise in K⁺ due to the opening of K⁺ channels in the single layer of endothelial cells and the efflux of K⁺ from the surrounding mass of smooth muscle cells due to K_ir channel and Na⁺-K⁺-ATPase activation.

	Other candidates for EDHF

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
In addition to the epoxides, anandamide, and endothelial K⁺, several other candidates have been proposed as EDHF. Thus reactive oxygen species such as the hydroxyl radical or hydrogen peroxide have been suggested, but evidence for this hypothesis is rather weak, as superoxide dismutase and catalase have little or no effect on EDHF-mediated relaxations in different vascular beds. The same holds true for carbon monoxide, in particular because oxyhemoglobin, an effective scavenger of carbon monoxide, does not affect NO/PGI₂-independent relaxation (3, 5, 10).

Moreover, an electrical coupling between endothelial and smooth muscle cells must be considered, especially for the microcirculation, in which the relative contribution of EDHF to endothelium-dependent vasodilatation appears to be much more prominent than in conduit arteries (3, 10). However, the apparently diffusible EDHF in conduit arteries may not necessarily represent a different relaxing principle from an electrical coupling between endothelium and vascular smooth muscle in the microcirculation. One compelling argument for this hypothesis is that, by way of sensing the filling state of inositol 1,4,5-trisphosphate-sensitive Ca²⁺ stores, an epoxygenase appears to be activated in endothelial cells that metabolizes arachidonic acid to one or several of the epoxyeicosatrienoic acids. These, in turn, activate endothelial cell K_Ca channels in an autocrine manner, thereby hyperpolarizing the endothelial cell membrane and, as a consequence, increasing the driving force for capacitative Ca²⁺ entry (7). In arterioles, this hyperpolarization could spread to the adjacent smooth muscle cells via myoendothelial gap junctions, thereby hyperpolarizing and hence relaxing these cells as well. This interesting hypothesis clearly warrants further investigation, which may, however, be hampered by the fact that gap junction-uncoupling agents such as halothane or octanol are rather difficult to employ in the microcirculation due to their various side effects. What seems more promising is the use of antisense oligodeoxynucleotides against the connexins that constitute the myoendothelial gap junctions (i.e., connexin 37, 40, and 43). Finally, acetylcholine-induced epoxyeicosatrienoic acid formation may also be a mechanism for the reported efflux of K⁺ from the endothelium of the hepatic and mesenteric arteries of the rat (4).

	Effects of hemodynamic forces on EDHF release

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
Of note in the studies with the perfused coronary artery segments was that an increase in transmural pressure in the donor segment augmented the EDHF-mediated hyperpolarization of the detector smooth muscle cells (11). In subsequent experiments, it was demonstrated that cyclic stretching of segments alone induced a proportional increase in the release of EDHF, and this effect was abolished when the donor segments had been pretreated with 17-ODYA (12). Because coronary arteries are unique in being continually deformed by the rhythmic contraction of the heart, it is conceivable, therefore, that cyclic deformation of the coronary endothelial cells, possibly by raising the intracellular concentration of Ca²⁺ and hence the phospholipase A₂-dependent liberation of arachidonic acid (cf. Fig. 1), elevates the formation of EDHF and in this way contributes to the regulation of coronary blood flow.

	Conclusion(s)

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
The aforementioned findings suggest that, in addition to PGI₂ and NO, the vascular endothelium releases a diffusible factor that hyperpolarizes and hence relaxes the adjacent smooth muscle cells of the media. In several vascular beds, in particular in coronary arteries (including human coronary arteries), this hyperpolarizing factor displays the typical pharmacological characteristics of a cytochrome P₄₅₀-derived arachidonic acid metabolite and exerts its effect by activating smooth muscle cell K_Ca channels. Since these cells are tightly coupled electrically, hyperpolarization of only a few or the first layer of smooth muscle cells by this factor may be sufficient to elicit a decrease in tension in the entire vessel wall. In addition to the epoxide-like EDHF in the coronary circulation, however, it is likely that other, possibly related, hyperpolarizing factors exist in different vascular beds or species.

	Clinical perspective

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 
Agonist-induced endothelium-dependent hyperpolarization in the coronary microcirculation may be a major determinant of arteriolar tone and hence of coronary blood flow. Inhibition of NO synthesis unmasks this dilator component, suggesting that, under physiological conditions, i.e., when the synthesis of NO is intact, endothelium-dependent hyperpolarization is suppressed (10). However, in situations where the synthesis or action of NO is reduced, such as in atherosclerosis, hypercholesterolemia, or ischemia, EDHF release evoked by local mediators or pulsatile stretch may become a crucial compensatory or reserve mechanism for the maintenance of nutritive myocardial blood flow (3, 5). In light of recent evidence that the enhanced formation of superoxide anions associated with these conditions not only leads to chemical inactivation of NO but also gives rise to the generation of peroxynitrite, a highly effective inhibitor of PGI₂ synthesis (Fig. 4; Ref. 15), this reserve mechanism may in fact be the last resort of the coronary circulation to escape a life-threatening vasospasm. To fulfill this function, however, both the synthesis and mechanism of action of EDHF must be insensitive to changes in the local concentration of superoxide anions or peroxynitrite, and indeed this seems to be the case. It is safe to conclude, therefore, that although its chemical nature has not yet been identified with certainty, EDHF is no longer a fiction but a fact and probably a clinically most important one.

View larger version (29K): [in this window] [in a new window]   FIGURE 4. Schematic view of proposed changes in endothelial autacoid production in coronary heart disease due to an increased formation of reactive oxygen species. PGH2, prostaglandin H2; ONOO-, peroxynitrite; O2-, superoxide anion.

	Acknowledgments

 
I must apologize to all those whose important contributions to the field of EDHF research I could not cite due to space constraints. Refs. 1, 3, 5, 10, 13, and 14 are review articles that refer to the majority of those original papers not mentioned here.

	References

Top Introduction Discovery of an endothelium... Mechanism of action Characterization of EDHF as... Epoxyeicosatrienoic acids Anandamide Endothelium-derived K+ Other candidates for EDHF Effects of hemodynamic forces... Conclusion(s) Clinical perspective References

 

1. Campbell, W. B., D. Gebremedhin, P. F. Pratt, and D. R. Harder. Identification of epoxyeicosa-trienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 78: 415–423, 1996.[Abstract/Free Full Text]
2. Chataigneau, T., M. Félétou, C. Thollon, N. Villeneuve, J.-P. Vilaine, J. Duhault, and P. M. Vanhoutte. Cannabinoid CB₁ receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat messenteric and porcine coronary arteries. Br. J. Pharmacol. 123: 968–974, 1998.[ISI][Medline]
3. Cohen, R. A., and P. M. Vanhoutte. Endothelium-dependent hyperpolarization: beyond nitric oxide and cyclic GMP. Circulation 92: 3337–3349, 1995.[Free Full Text]
4. Edwards, G., K. A. Dora, M. J. Gardener, C. J. Garland, and A. H. Weston. K⁺ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396: 269–272, 1998.[Medline]
5. Garland, C. J., F. Plane, B. K. Kemp, and T. M. Cocks. Endothelium-dependent hyperpolarization: a role in the control of vascular tone. Trends Pharmacol. Sci. 16: 23–30, 1995.[Medline]
6. Gebremedhin, D., D. R. Harder, P. F. Pratt, and W. B. Campbell. Bioassay of an endothelium-derived hyperpolarizing factor from bovine coronary arteries: role of a cytochrome P₄₅₀ metabolite. J. Vasc. Res. 35: 274–284, 1998.[ISI][Medline]
7. Graier, W. F., S. Simecek, and M. Sturek. Cytochrome P₄₅₀ mono-oxygenase-regulated signalling of Ca²⁺ entry in human and bovine endothelial cells. J. Physiol. (Lond.) 482: 259–274, 1995.[ISI][Medline]
8. Li, P., A. Zou, and W. B. Campbell. Regulation of potassium channels in coronary arterial smooth muscle by endothelium-derived vasodilators. Hypertension 29: 262–267, 1997.[Abstract/Free Full Text]
9. Lischke, V., R. Busse, and M. Hecker. Selective inhibition by barbiturates of the synthesis of endothelium-derived hyperpolarizing factor in the rabbit carotid artery. Br. J. Pharmacol. 115: 969–974, 1995.[ISI][Medline]
10. Mombouli, J. V., and P. M. Vanhoutte. Endothelium-derived hyperpolarizing factor(s): updating the unknown. Trends Pharmacol. Sci. 18: 252–256, 1997.[Medline]
11. Popp, R., J. Bauersachs, M. Hecker, I. Fleming, and R. Busse. A transferable, ß-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J. Physiol. (Lond.) 497: 699–709, 1996.[ISI][Medline]
12. Popp, R., I. Fleming, and R. Busse. Pulsatile stretch in coronary arteries elicits release of endothelium-derived hyperpolarizing factor: a modulator of arterial compliance. Circ. Res. 82: 696–703, 1998.[Abstract/Free Full Text]
13. Quilley, J., D. Fulton, and J. C. McGiff. Hyperpolarizing factors. Biochem. Pharmacol. 54: 1059–1070, 1997.[ISI][Medline]
14. Randall, M. D., and D. A. Kendall. Endocannabinoids: a new class of vasoactive substances. Trends Pharmacol. Sci. 19: 55–58, 1998.[Medline]
15. Zou, M. H., and V. Ullrich. Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett. 382: 101–104, 1996.[ISI][Medline]

This article has been cited by other articles:

				Y. Park, S. Capobianco, X. Gao, J. R. Falck, K. C. Dellsperger, and C. Zhang Role of EDHF in type 2 diabetes-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1982 - H1988. [Abstract] [Full Text] [PDF]

				M. Kajiya, M. Hirota, Y. Inai, T. Kiyooka, T. Morimoto, T. Iwasaki, K. Endo, S. Mohri, J. Shimizu, T. Yada, et al. Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2737 - H2744. [Abstract] [Full Text] [PDF]

				A. C. Santos, M. J. N. N. Alves, M. U. P. B. Rondon, A. C. P. Barretto, H. R. Middlekauff, and C. E. Negrao Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H593 - H599. [Abstract] [Full Text] [PDF]

				E Rousseau, M. Cloutier, C. Morin, and S. Proteau Capsazepine, a vanilloid antagonist, abolishes tonic responses induced by 20-HETE on guinea pig airway smooth muscle Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L460 - L470. [Abstract] [Full Text] [PDF]

				L. Luksha, H. Nisell, and K. Kublickiene The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1102 - R1109. [Abstract] [Full Text] [PDF]

				T. A. Stekiel, Z. J. Bosnjak, and W. J. Stekiel Effects of General Anesthetics on Regulation of the Peripheral Vasculature Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 311 - 331. [Abstract] [PDF]

				R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]

				E. M. Golding and T. E. Kepler Role of estrogen in modulating EDHF-mediated dilations in the female rat middle cerebral artery Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2417 - H2423. [Abstract] [Full Text] [PDF]

				C. Benoit, B. Renaudon, D. Salvail, and E. Rousseau EETs relax airway smooth muscle via an EpDHF effect: BKCa channel activation and hyperpolarization Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L965 - L973. [Abstract] [Full Text] [PDF]

				D. Salvail, M. Cloutier, and E. Rousseau Functional reconstitution of an eicosanoid-modulated Cl- channel from bovine tracheal smooth muscle Am J Physiol Cell Physiol, March 1, 2002; 282(3): C567 - C577. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (31) Citing Articles via Google Scholar Google Scholar Articles by Hecker, M. Search for Related Content PubMed PubMed Citation Articles by Hecker, M.