© 1999 American Heart Association, Inc.
Editorial |
Endothelium-Derived Hyperpolarizing Factors and Vascular Cytochrome P450 Metabolites of Arachidonic Acid in the Regulation of Tone
From the Departments of Pharmacology and Toxicology and Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail wbcamp{at}mcw.edu
Key Words: epoxyeicosatrienoic acid • 20-hydroxyeicosatetraenoic acid • K+ channel
The discovery of prostacyclin and its endothelial origin established the idea of endothelium-derived vasoactive eicosanoids and led to the realization that endothelial cells were a source of autacoids that regulate vascular tone.1 2 In 1980, Furchgott and Zawadzki3 described endothelium-derived relaxing factor (EDRF) and presented evidence that EDRF was a lipoxygenase metabolite of arachidonic acid. Subsequent research indicated that EDRF was nitric oxide.4 Several laboratories have described an endothelium-derived vasodilating factor that is distinct from nitric oxide or prostacyclin.5 6 7 8 9 10 These laboratories reported that acetylcholine caused endothelium-dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxations and hyperpolarizations were not altered by arginine analogs that inhibit nitric oxide synthase or inhibitors of cyclooxygenase or lipoxygenases. They were blocked by inhibitors of calcium-activated potassium channels such as tetraethylammonium or charybdotoxin but not by inhibitors of ATP-sensitive potassium channels such as glibenclamide. Subsequent studies indicated that this factor was released by other agonists including bradykinin and substance P. It was concluded that this vasodilating factor acts by opening calcium-activated potassium channels and hyperpolarizing the smooth muscle membrane. This factor has been termed endothelium-derived hyperpolarizing factor or EDHF.
The article by Thollon and coworkers11 in this issue of Circulation Research further emphasizes the importance of EDHF in normal coronary arteries and arteries with regenerated endothelium. Several important insights are provided into the action and nature of EDHF by this work. First, this study demonstrates the importance of measuring membrane potential in defining the contribution of EDHF to the action of agonists. Hyperpolarization of vascular smooth muscle unequivocally defines EDHF activity. Second, the study indicates the importance of the resting membrane potential of the smooth muscle on the magnitude of the response to EDHF. Removal of the endothelial lining of porcine coronary arteries results in depolarization of the underlying vascular smooth muscle cells, suggesting a tonic hyperpolarizing influence of the endothelium. When the endothelium is allowed to regenerate, the hyperpolarizations to serotonin are abolished while the hyperpolarizations to bradykinin are preserved. The arteries with the less negative membrane potentials exhibit the greatest hyperpolarizations to bradykinin. Third, there are fundamental differences in the vascular effects of serotonin and bradykinin. Serotonin induces vascular smooth muscle hyperpolarizations of 3 to 13 mV that are transient in duration. In contrast, bradykinin hyperpolarizes the coronary smooth muscle by 40 mV at the highest concentration of the peptide, and the hyperpolarizations are long lasting. The authors raise the possibility that different EDHFs mediate the responses to these two agonists. Bradykinin clearly acts to hyperpolarize coronary arterial smooth muscle through the release of a transferable endothelial factor that activates calcium-activated potassium channels.12 13 14 Serotonin has not been as extensively studied. This Editorial will examine the possible identity of EDHF(s), the need to apply chemical, biochemical, electrophysiological, and pharmacological approaches to defining EDHF and the importance of the experimental conditions in interpreting these studies.
Many studies define EDHF activity as relaxations to an agonist in the presence of inhibitors of nitric oxide synthase and prostaglandin synthase. However, it should be emphasized that endothelium-dependent hyperpolarization of smooth muscle is the hallmark of EDHF activity. Thollon and coworkers11 emphasize this point by demonstrating that agonist-induced changes in membrane potential may be dissociated from mechanical activity of the vessel. Serotonin produces small, transient hyperpolarizations but sustained relaxations.11 15 The possibility must always be considered that endothelial factors other than a hyperpolarizing factor may mediate relaxations that are resistant to inhibitors of nitric oxide and prostaglandin synthase.
Thollon and coworkers11 also emphasize the importance of the resting membrane potential on the magnitude of the response to agonists that release EDHF and the influence of the experimental conditions on these electrical events. The resting membrane potential of arteries pinned to a supporting matrix in the present study is markedly different from arteries under physiological transmural pressures.16 Arterial smooth muscle cells of pressurized coronary arteries exhibiting physiological transmural pressures are depolarized compared with arteries under nonpressurized conditions.17 18 Furthermore, pressurization of arteries activates second messenger systems that can alter the active state of arterial smooth muscle and endothelial smooth muscle interactions.17 19 The response to agonists that release EDHF should be enhanced in pressurized and depolarized arteries. Thus, the experimental conditions may minimize or emphasize the role of EDHF.
The identity of EDHF and the possibility of multiple EDHFs have
received considerable attention.20 21 22 Recent studies from
a number of laboratories have shown that in coronary, cerebral,
and renal arteries EDHF is a cytochrome P450 metabolite of
arachidonic acid, an epoxyeicosatrienoic acid or
EET12 13 14 23 24 25 26 27 (Figure
). Endothelial
cells metabolize arachidonic acid by the
cyclooxygenase, lipoxygenase, and
cytochrome P450 metabolic pathways.28 29 The
EETs are the only cytochrome P450 metabolites of
arachidonic acid produced by the
endothelial cell.29 The cytochrome P450
isozyme of the endothelial cell appears to be a CYP 2C
epoxygenase.30 The EETs are released by
vasoactive substances such as acetylcholine or bradykinin as well as
arachidonic acid. They activate
calcium-activated potassium channels and hyperpolarize and
relax vascular smooth muscle. Arteries from other vascular beds such as
the guinea pig carotid artery and rat mesenteric artery also exhibit
EDHF activity; however, this activity is not reduced by
inhibitors of cytochrome P450.31 32 33 The
reason for this discrepancy may lie in the fact that EETs are not the
only cytochrome P450 metabolites of arachidonic acid
produced by the blood vessel. Smooth muscle cells do not synthesize
EETs but rather metabolize arachidonic acid by
cytochrome P450 to
20-hydroxyeicosatetraenoic acid
(20-HETE)34 35 36
(Figure). This reaction is
catalyzed by a CYP 4A isozyme, an 
-hydroxylase. This metabolite is
made by the smooth muscle of renal and cerebral vessels but not
coronary arteries. 20-HETE has the opposite effects of the EETs
on vascular tone, membrane potential, and potassium channel activity.
It inhibits the opening of the calcium-activated potassium
channel, depolarizes the cell, increases intracellular calcium, and
vasoconstricts vascular smooth muscle.34 35 37 Unlike the
EETs that act as a transferable paracrine factor,12 13 14
20-HETE acts as an intracellular second messenger in smooth muscle. It
is released in response to stretch or increases in transmural pressure
and is proposed to mediate myogenic tone.35 36
|
There are a number of drugs that inhibit cytochrome P450
including clotrimazole, miconazole, SKF525A, metyrapone, and
17-octadecyoic acid (17-ODYA).38 39 40 These drugs are
equally active in inhibiting the CYP 2C epoxygenase, and
CYP 4A -hydroxylase isozymes so inhibit both EET and 20-HETE
synthesis in blood vessels. In the coronary artery, the
endothelium produces EETs; however, 20-HETE is not made
by the coronary smooth muscle.23 29 As a result,
inhibitors of cytochrome P450 clearly inhibit the
relaxations and hyperpolarizations to
acetylcholine, bradykinin, and arachidonic acid,
indicating that a cytochrome P450–derived factor mediates these smooth
muscle effects.23 24 26 27 In contrast, with CYP 2C
producing vasodilatory EETs in the endothelium and CYP
4A producing the vasoconstrictor 20-HETE in the smooth muscle, it is
not surprising that inhibitors of cytochrome P450 give
variable results in vessels that produce both of these eicosanoids.
If the vessel produces both EETs and 20-HETE, the action of an
inhibitor of cytochrome P450 will depend on which of the
two cytochrome P450 pathways predominate. For example, if there is
stretch on the vessel or if pressurized vessels are studied, the CYP
4A–derived 20-HETE pathway will predominate with closure of the
calcium-activated potassium channel, depolarization, and
vasoconstriction. An inhibitor of cytochrome P450 will
decrease 20-HETE synthesis, open the potassium channel, hyperpolarize
the smooth muscle, and relax the vessel.34 37 This effect
of the cytochrome P450 inhibitor will mimic the activity of
EDHF. Agonists that release EDHF will compete with 20-HETE for control
of the calcium-activated potassium channel and membrane
potential. Inhibitors of cytochrome P450 will inhibit both
pathways, and the effect on membrane potential and vascular tone may be
minimal. This finding may be interpreted to indicate that
inhibitors of cytochrome P450 have direct effects on smooth
muscle and on potassium channel activity and do not block the activity
of EDHF. Under conditions of low 20-HETE synthesis, the effects of the
endothelial EETs will predominate. Agonists that
release EETs and EDHF will open calcium-activated potassium
channels and hyperpolarize and relax the smooth muscle.
Inhibitors of cytochrome P450 will block EET
production, inhibit potassium channel activation, and prevent
the hyperpolarization and
relaxation.24 25 27 These findings with the
inhibitors would indicate that EDHF is a cytochrome P450
metabolite.
Some inhibitors of cytochrome P450 have direct effects on potassium channels.41 42 43 Clotrimazole and ketoconazole inhibit calcium-activated potassium channels in vascular smooth muscle, colonic cells, and leukemia cells. The inhibition by these drugs occurred in whole-cell recordings and in recordings from outside-out patches. Thus, the drugs do not require intracellular second messengers or eicosanoids but appear to have direct effects on the channel. Whereas the imidazole portion of the molecule is required to interact with the heme and inhibit cytochrome P450, the imidazole ring is not required for potassium channel inhibition. Thus, inhibition of cytochrome P450 is not necessary for channel inhibition. The channel inhibition may be specific to these drugs and may not be generalized to other inhibitors of cytochrome P450. For example, in coronary artery smooth muscle cells, miconazole and SKF525A failed to alter calcium-activated potassium channel activity in inside-out patches when used in concentrations that inhibited the metabolism of arachidonic acid by cytochrome P450.23 27 In summary, some inhibitors of cytochrome P450 block the calcium-activated potassium channel while other do not. It is important to test the inhibitors for direct effects on the channels using inside-out or outside-out patches, cell-free states, to eliminate the contribution of endogenous cytochrome P450 metabolites of arachidonic acid. High concentration of any inhibitor may have nonspecific effects such as potassium channel inhibition. As a result, it is important to determine the concentrations of the inhibitors that block the metabolism of arachidonic acid by cytochrome P450 and determine if the same concentrations alter potassium channel activity. Once the specificity of the inhibitor is established, the drug may be used to determine the contribution of cytochrome P450 metabolites in the regulation of ion channels and vascular tone, ie, EDHF activity.
Several investigators have found that SKF525A, miconazole, ketoconazole, and clotrimazole blocked relaxations and hyperpolarizations to the potassium channel openers pinacidil and cromakalim as well as acetylcholine.32 33 44 17-ODYA and 1-aminobenzotriazole were without effect. Unfortunately, none of these studies verified that the concentrations of the inhibitors tested inhibited cytochrome P450–mediated metabolism of arachidonic acid. These authors concluded that some inhibitors of cytochrome P450 had nonspecific effects on the ATP-sensitive potassium channel activated by pinacidil and cromakalim. However, an alternative explanation should be considered. Arachidonic acid has direct effects on ATP-sensitive potassium channels.45 46 47 The fatty acid stimulates the channel in the presence of ATP but inhibits the channel in the absence of ATP with an IC50 of 3.8 µmol/L. Pinacidil and cromakalim appear to activate the channel by decreasing the sensitivity of the channel to ATP.48 Thus, these potassium channel openers mimic the low ATP state of the channel, and arachidonic acid would be expected to inhibit the channel under these conditions. Inhibition of cytochrome P450 will decrease the formation of arachidonic acid metabolites leaving more free arachidonic acid to inhibit the channel. Such a mechanism may represent an alternative explanation for the ability of cytochrome P450 inhibitors to inhibit the effects of potassium channel openers.
Although arachidonic acid metabolism has been studied in the bovine coronary artery, canine renal artery, rabbit aorta, rabbit carotid, and cat cerebral artery,29 34 35 49 this is not the case for arteries from other vascular beds. EDHF activity has been reported in the guinea pig and rabbit carotid artery, rabbit aorta, rat mesenteric artery, rat portal vein, and rat hepatic artery.9 31 50 51 52 The rabbit carotid artery and rabbit aorta have EDHF activity but do not produce metabolites of arachidonic acid by the cytochrome P450 pathway.49 Thus, some other compound(s), possibly nitric oxide or another metabolite of arachidonic acid, may mediate the effect.52 53 54 In the rat mesenteric artery, inconsistent effects have been reported with inhibitors of cytochrome P450.32 33 55 Under some conditions, the inhibitors of cytochrome P450 block acetylcholine-induced relaxations and hyperpolarizations, and induction of cytochrome P450 enhances these effects.55 In other studies, inhibitors of cytochrome P450 do not alter acetylcholine-induced relaxations or hyperpolarizations.33 None of these studies documents that the drugs inhibited the metabolism of arachidonic acid by cytochrome P450. The absence of biochemical studies of arachidonic acid metabolism in these vessels makes interpretation of the data impossible. It is not known whether these vessels metabolize arachidonic acid by cytochrome P450, whether they metabolize arachidonic acid to EETs and/or 20-HETE, or whether the drugs inhibit cytochrome P450 metabolism of arachidonic acid in the concentrations used. Potassium ion and anandamide are proposed as EDHFs in this vascular bed.56 57
In summary, the studies of Thollon and coworkers11 emphasize the importance of measuring membrane potential of vascular smooth muscle in defining the endothelium-dependent response to an agonist as mediated by EDHF. The experimental conditions may determine the magnitude of the contribution of EDHF to an agonist response by setting the resting membrane potential. Depolarization of the arteries by pressurization or regeneration of the endothelium will enhance the EDHF response.11 Evidence from several sources suggests that there are multiple EDHFs and that the chemical mediator of the EDHF response may vary with the vascular bed.20 21 22 In coronary, renal, and cerebral arteries, EETs appear to have the properties associated with the activity termed EDHF.12 23 24 25 26 27 In other vessels such as the rabbit carotid artery and aorta, arachidonic acid is not metabolized by cytochrome P450, so other factors must mediate the hyperpolarization and vasorelaxation.49 52 53 54 In the guinea pig carotid artery, rat mesenteric artery, hepatic artery, and portal vein, there is a lack of biochemical information on arachidonic acid metabolism to allow a determination of whether an arachidonic acid metabolite or another mediator is involved. Thus, it must be stressed that when studying the physiology and pharmacology of the vascular cytochrome P450 pathway(s), the arachidonic acid metabolites produced by the smooth muscle cells and endothelial cells must be known. Without a clear biochemical definition of the metabolites produced, a rational interpretation of the results with inhibitors or inducers is not possible.
Acknowledgments
The authors thank Gretchen Barg for her secretarial assistance. These studies were supported by grants from the National Heart, Lung and Blood Institute (HL-51055 and HL-37981).
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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A. Dhanasekaran, S. K. Gruenloh, J. N. Buonaccorsi, R. Zhang, G. J. Gross, J. R. Falck, P. K. Patel, E. R. Jacobs, and M. Medhora Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H724 - H735. [Abstract] [Full Text] [PDF]
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T. C. DeLozier, G. E. Kissling, S. J. Coulter, D. Dai, J. F. Foley, J. A. Bradbury, E. Murphy, C. Steenbergen, D. C. Zeldin, and J. A. Goldstein Detection of Human CYP2C8, CYP2C9, and CYP2J2 in Cardiovascular Tissues Drug Metab. Dispos., April 1, 2007; 35(4): 682 - 688. [Abstract] [Full Text] [PDF]
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W. B. Campbell and J. R. Falck Arachidonic Acid Metabolites as Endothelium-Derived Hyperpolarizing Factors Hypertension, March 1, 2007; 49(3): 590 - 596. [Abstract] [Full Text] [PDF]
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 T. L. Domeier and S. S. Segal Electromechanical and pharmacomechanical signalling pathways for conducted vasodilatation along endothelium of hamster feed arteries J. Physiol., February 15, 2007; 579(1): 175 - 186. [Abstract] [Full Text] [PDF]
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D. Ye, W. Zhou, T. Lu, S. G. Jagadeesh, J. R. Falck, and H.-C. Lee Mechanism of rat mesenteric arterial KATP channel activation by 14,15-epoxyeicosatrienoic acid Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1326 - H1336. [Abstract] [Full Text] [PDF]
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D. Biyashev, F. Tan, Z. Chen, K. Zhang, P. A. Deddish, E. G. Erdos, and C. Hecquet Kallikrein activates bradykinin B2 receptors in absence of kininogen Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1244 - H1250. [Abstract] [Full Text] [PDF]
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K. M. Gauthier, E. M. Edwards, J. R. Falck, D. S. Reddy, and W. B. Campbell 14,15-Epoxyeicosatrienoic Acid Represents a Transferable Endothelium-Dependent Relaxing Factor in Bovine Coronary Arteries Hypertension, April 1, 2005; 45(4): 666 - 671. [Abstract] [Full Text] [PDF]
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X. Zhao, A. Dey, O. P. Romanko, D. W. Stepp, M.-H. Wang, Y. Zhou, L. Jin, J. S. Pollock, R. C. Webb, and J. D. Imig Decreased epoxygenase and increased epoxide hydrolase expression in the mesenteric artery of obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R188 - R196. [Abstract] [Full Text] [PDF]
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D. Ye, W. Zhou, and H.-C. Lee Activation of rat mesenteric arterial KATP channels by 11,12-epoxyeicosatrienoic acid Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H358 - H364. [Abstract] [Full Text] [PDF]
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T. Ohta, N. Hasebe, S. Tsuji, K. Izawa, Y.-T. Jin, S. Kido, S. Natori, M. Sato, and K. Kikuchi Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2914 - H2921. [Abstract] [Full Text] [PDF]
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Y. Kansui, K. Fujii, K. Nakamura, K. Goto, H. Oniki, I. Abe, Y. Shibata, and M. Iida Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H216 - H224. [Abstract] [Full Text] [PDF]
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M. Tanaka, H. Kanatsuka, B.-H. Ong, T. Tanikawa, A. Uruno, T. Komaru, R. Koshida, and K. Shirato Cytochrome P-450 metabolites but not NO, PGI2, and H2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1939 - H1948. [Abstract] [Full Text] [PDF]
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X. Zhao, D. M. Pollock, D. C. Zeldin, and J. D. Imig Salt-Sensitive Hypertension After Exposure to Angiotensin Is Associated With Inability to Upregulate Renal Epoxygenases Hypertension, October 1, 2003; 42(4): 775 - 780. [Abstract] [Full Text] [PDF]
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 D. Striimper, M. Durieux, and P. Roekaerts Endothelial and Microvascular Function Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 225 - 238. [Abstract] [PDF]
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 M. Potente, B. Fisslthaler, R. Busse, and I. Fleming 11,12-Epoxyeicosatrienoic Acid-induced Inhibition of FOXO Factors Promotes Endothelial Proliferation by Down-Regulating p27Kip1 J. Biol. Chem., August 8, 2003; 278(32): 29619 - 29625. [Abstract] [Full Text] [PDF]
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K. Nakagawa, J. S. Marji, M. L. Schwartzman, M. R. Waterman, and J. H. Capdevila Androgen-mediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R1055 - R1062. [Abstract] [Full Text] [PDF]
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S. Gschwend, R. H. Henning, D. de Zeeuw, and H. Buikema Coronary Myogenic Constriction Antagonizes EDHF-Mediated Dilation: Role of KCa Channels Hypertension, April 1, 2003; 41(4): 912 - 918. [Abstract] [Full Text] [PDF]
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X. Zhao, D. M. Pollock, E. W. Inscho, D. C. Zeldin, and J. D. Imig Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension Hypertension, March 1, 2003; 41(3): 709 - 714. [Abstract] [Full Text] [PDF]
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T. Lu, M. VanRollins, and H.-C. Lee Stereospecific Activation of Cardiac ATP-Sensitive K+ Channels by Epoxyeicosatrienoic Acids: A Structural Determinant Study Mol. Pharmacol., November 1, 2002; 62(5): 1076 - 1083. [Abstract] [Full Text] [PDF]
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H. C. Seegers, R. W. Gross, and W. A. Boyle Calcium-Independent Phospholipase A2-Derived Arachidonic Acid Is Essential for Endothelium-Dependent Relaxation by Acetylcholine J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 918 - 923. [Abstract] [Full Text] [PDF]
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F. Xu, W. O. Straub, W. Pak, P. Su, K. G. Maier, M. Yu, R. J. Roman, P. R. Ortiz De Montellano, and D. L. Kroetz Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid omega -hydroxylase activity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R710 - R720. [Abstract] [Full Text] [PDF]
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G. G. Emerson, T. O. Neild, and S. S. Segal Conduction of hyperpolarization along hamster feed arteries: augmentation by acetylcholine Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H102 - H109. [Abstract] [Full Text] [PDF]
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N. J. Alkayed, T. Goyagi, H.-D. Joh, J. Klaus, D. R. Harder, R. J. Traystman, and P. D. Hurn Neuroprotection and P450 2C11 Upregulation After Experimental Transient Ischemic Attack Stroke, June 1, 2002; 33(6): 1677 - 1684. [Abstract] [Full Text] [PDF]
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J. Sun, X. Sui, J. A. Bradbury, D. C. Zeldin, M. S. Conte, and J. K. Liao Inhibition of Vascular Smooth Muscle Cell Migration by Cytochrome P450 Epoxygenase-Derived Eicosanoids Circ. Res., May 17, 2002; 90(9): 1020 - 1027. [Abstract] [Full Text] [PDF]
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K. M. Gauthier, C. Deeter, U. M. Krishna, Y. K. Reddy, M. Bondlela, J.R. Falck, and W. B. Campbell 14,15-Epoxyeicosa-5(Z)-enoic Acid: A Selective Epoxyeicosatrienoic Acid Antagonist That Inhibits Endothelium-Dependent Hyperpolarization and Relaxation in Coronary Arteries Circ. Res., May 17, 2002; 90(9): 1028 - 1036. [Abstract] [Full Text] [PDF]
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R. L. Hester and L. W. Hammer Venular-arteriolar communication in the regulation of blood flow Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1280 - R1285. [Abstract] [Full Text] [PDF]
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 T. M. Griffith, A. T. Chaytor, H. J. Taylor, B. D. Giddings, and D. H. Edwards cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions PNAS, April 30, 2002; 99(9): 6392 - 6397. [Abstract] [Full Text] [PDF]
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L. M. King, J. Ma, S. Srettabunjong, J. Graves, J. A. Bradbury, L. Li, M. Spiecker, J. K. Liao, H. Mohrenweiser, and D. C. Zeldin Cloning of CYP2J2 Gene and Identification of Functional Polymorphisms Mol. Pharmacol., April 1, 2002; 61(4): 840 - 852. [Abstract] [Full Text] [PDF]
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R E Haddock, G D S Hirst, and C E Hill Voltage independence of vasomotion in isolated irideal arterioles of the rat J. Physiol., April 1, 2002; 540(1): 219 - 229. [Abstract] [Full Text] [PDF]
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A. T. Chaytor, H. J. Taylor, and T. M. Griffith Gap junction-dependent and -independent EDHF-type relaxations may involve smooth muscle cAMP accumulation Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1548 - H1555. [Abstract] [Full Text] [PDF]
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B. Lauterbach, E. Barbosa-Sicard, M.-H. Wang, H. Honeck, E. Kargel, J. Theuer, M. L. Schwartzman, H. Haller, F. C. Luft, M. Gollasch, et al. Cytochrome P450-Dependent Eicosapentaenoic Acid Metabolites Are Novel BK Channel Activators Hypertension, February 1, 2002; 39(2): 609 - 613. [Abstract] [Full Text] [PDF]
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B. Yang, L. Graham, S. Dikalov, R. P. Mason, J. R. Falck, J. K. Liao, and D. C. Zeldin Overexpression of Cytochrome P450 CYP2J2 Protects against Hypoxia-Reoxygenation Injury in Cultured Bovine Aortic Endothelial Cells Mol. Pharmacol., August 1, 2001; 60(2): 310 - 320. [Abstract] [Full Text] [PDF]
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T. Lu, P. V G Katakam, M. VanRollins, N. L Weintraub, A. A Spector, and H.-C. Lee Dihydroxyeicosatrienoic acids are potent activators of Ca2+-activated K+ channels in isolated rat coronary arterial myocytes J. Physiol., August 1, 2001; 534(3): 651 - 667. [Abstract] [Full Text] [PDF]
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W. B. Campbell and D. R. Harder Prologue: EDHF-what is it? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2413 - H2416. [Full Text] [PDF]
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Y. Zhang, C. L. Oltman, T. Lu, H.-C. Lee, K. C. Dellsperger, and M. VanRollins EET homologs potently dilate coronary microvessels and activate BKCa channels Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2430 - H2440. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, M. A. Carroll, H. Jiang, C. J. Smith, J. A. Connetta, J. R. Falck, E. G. Shesely, A. Koller, and G. Kaley EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2462 - H2469. [Abstract] [Full Text] [PDF]
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H. A. Coleman, M. Tare, and H. C. Parkington EDHF is not K+ but may be due to spread of current from the endothelium in guinea pig arterioles Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2478 - H2483. [Abstract] [Full Text] [PDF]
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R. Rastaldo, N. Paolocci, A. Chiribiri, C. Penna, D. Gattullo, and P. Pagliaro Cytochrome P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2823 - H2832. [Abstract] [Full Text] [PDF]
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O. Platoshyn, Y. Yu, V. A. Golovina, S. S. McDaniel, S. Krick, L. Li, J.-Y. Wang, Lewis. J. Rubin, and J. X.-J. Yuan Chronic hypoxia decreases KV channel expression and function in pulmonary artery myocytes Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L801 - L812. [Abstract] [Full Text] [PDF]
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Z. Yu, F. Xu, L. M. Huse, C. Morisseau, A. J. Draper, J. W. Newman, C. Parker, L. Graham, M. M. Engler, B. D. Hammock, et al. Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids Circ. Res., November 24, 2000; 87(11): 992 - 998. [Abstract] [Full Text] [PDF]
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S. Sasaki, K. Daitoku, A. Iwasa, and S. Motomura NO is involved in MCh-induced accentuated antagonism via type II PDE in the canine blood-perfused SA node Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2509 - H2518. [Abstract] [Full Text] [PDF]
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G. G. Emerson and S. S. Segal Electrical Coupling Between Endothelial Cells and Smooth Muscle Cells in Hamster Feed Arteries : Role in Vasomotor Control Circ. Res., September 15, 2000; 87(6): 474 - 479. [Abstract] [Full Text] [PDF]
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R. P. Brandes, F.-H. Schmitz-Winnenthal, M. Feletou, A. Godecke, P. L. Huang, P. M. Vanhoutte, I. Fleming, and R. Busse An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice PNAS, August 15, 2000; 97(17): 9747 - 9752. [Abstract] [Full Text] [PDF]
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B. M. Marcic and E. G. Erdös Protein Kinase C and Phosphatase Inhibitors Block the Ability of Angiotensin I-Converting Enzyme Inhibitors to Resensitize the Receptor to Bradykinin without Altering the Primary Effects of Bradykinin J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 605 - 612. [Abstract] [Full Text]
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R. S. Barlow, A. M. El-Mowafy, and R. E. White H2O2 opens BKCa channels via the PLA2-arachidonic acid signaling cascade in coronary artery smooth muscle Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H475 - H483. [Abstract] [Full Text] [PDF]
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M. J VanWijk, K. Kublickiene, K. Boer, and E. VanBavel Vascular function in preeclampsia Cardiovasc Res, July 1, 2000; 47(1): 38 - 48. [Abstract] [Full Text] [PDF]
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D. G. Welsh and S. S. Segal Role of EDHF in conduction of vasodilation along hamster cheek pouch arterioles in vivo Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1832 - H1839. [Abstract] [Full Text] [PDF]
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P. Pagliaro, N. Paolocci, T. Isoda, W. F Saavedra, G. Sunagawa, and D. A Kass Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide Cardiovasc Res, March 1, 2000; 45(4): 1001 - 1009. [Abstract] [Full Text] [PDF]
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S. L. Sandow and C. E. Hill Incidence of Myoendothelial Gap Junctions in the Proximal and Distal Mesenteric Arteries of the Rat Is Suggestive of a Role in Endothelium-Derived Hyperpolarizing Factor-Mediated Responses Circ. Res., February 18, 2000; 86(3): 341 - 346. [Abstract] [Full Text] [PDF]
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J. H. Capdevila, J. R. Falck, and R. C. Harris Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase J. Lipid Res., February 1, 2000; 41(2): 163 - 181. [Abstract] [Full Text]
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I. S. Bartlett and S. S. Segal Resolution of smooth muscle and endothelial pathways for conduction along hamster cheek pouch arterioles Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H604 - H612. [Abstract] [Full Text] [PDF]
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K. Node, X.-L. Ruan, J. Dai, S.-X. Yang, L. Graham, D. C. Zeldin, and J. K. Liao Activation of Galpha s Mediates Induction of Tissue-type Plasminogen Activator Gene Transcription by Epoxyeicosatrienoic Acids J. Biol. Chem., May 4, 2001; 276(19): 15983 - 15989. [Abstract] [Full Text] [PDF]
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T. M. Griffith, A. T. Chaytor, H. J. Taylor, B. D. Giddings, and D. H. Edwards cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions PNAS, April 30, 2002; 99(9): 6392 - 6397. [Abstract] [Full Text] [PDF]
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R. E. Haddock, G. D .S. Hirst, and C.E. Hill Voltage independence of vasomotion in isolated irideal arterioles of the rat J. Physiol., February 22, 2002; (2002) 200101369. [Abstract] [PDF]
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