(Hypertension. 1997;29:262.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Regulation of Potassium Channels in Coronary Arterial Smooth Muscle by Endothelium-Derived Vasodilators
From the Departments of Pharmacology and Toxicology and of Physiology, Medical College of Wisconsin, Milwaukee.
Reprint requests to Pin-Lan Li, MD, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail pli{at}post.its.mcw.edu
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Abstract |
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Recent studies have suggested that coronary endothelial cells produce and release nitric oxide (NO), prostaglandin I2, and epoxyeicosatrienoic acids (EETs). These endothelium-derived vasodilators play an important role in the control of coronary vascular tone. However, the mechanism by which these endothelium-derived vasodilators cause relaxation of coronary arterial smooth muscle has yet to be determined. This study characterized and compared the effects of NO, prostaglandin I2, and 11,12-EET on the two main types of potassium channels in small bovine coronary arterial smooth muscle: the large conductance Ca2+-activated K+ channels (KCa) and 4-aminopyridine-sensitive delayed rectifier K+ channels (Kdrf). In cell-attached patches, non-oate, an NO donor, activated both KCa and Kdrf channels. The open probability of both KCa and Kdrf channels increased 10- to 25-fold when nonoate was added to the bath at concentrations of 10-6 to 10-4 mol/L. 11,12-EET (10-8 to 10-4 mol/L) also increased the activity of the KCa channels in a concentration-dependent manner, but it had no effect on the activity of the Kdrf channels, even in the highest concentration studied (10-4 mol/L). In contrast to the effect of 11,12-EET, iloprost, a prostaglandin I2 analogue (10-6 to 10-4 mol/L), produced a concentration-dependent increase in the activity of Kdrf channels without affecting the KCa channels. In conclusion, all three endothelium-derived vasodilators act to open potassium channels; however, the channel types that they affect are different. NO activates both KCa and Kdrf channels; 11,12-EET activates only the KCa channels; and prostaglandin I2 activates only the Kdrf channels.
Key Words: potassium channels • nitric oxide • prostacyclin • epoxyeicosatrienoic acids • endothelium • coronary artery
Abbreviations: EET = epoxyeicosatrienoic acid • KCa = Ca2+-activated K+ channel • Kdrf = delayed rectifier K+ channel • NO = nitric oxide • NPo = channel open probability • PGI2 = prostaglandin I2 (prostacyclin)
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Introduction |
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The vascular endothelium plays an important role in the regulation of vascular tone, leukocyte function, and platelet aggregation.1–3 One aspect of the complex regulatory activities of the vascular endothelium is the production of endothelium-derived vasodilators, which act as mediators in the regulation of vascular tone.1 Recent studies have indicated that PGI2, NO, and EETs mediate endothelium-dependent vasodilation induced by various stimuli, such as bradykinin, acetylcholine, and shear stress.2–7 In this regard, PGI2 and NO have been considered as endothelium-derived relaxation factors1,2,8 and EET as an endothelium-derived hyperpolarization factor.7 Since potassium channels in vascular smooth muscle are targets for the effect of many vasodilators, it remains to be determined whether activation of K+ channels also mediates the effects of these endothelium-derived vasodilators. Although increases in cAMP and cGMP have been reported to be associated with the effect of PGI2 and NO, respectively, K+ channels cannot be excluded as an important effector, since cAMP-dependent and cGMP-dependent protein kinases activate K+ channels in vascular smooth muscle.9 Furthermore, PGI2, NO, and EETs have been reported to hyperpolarize vascular smooth muscle.3,7,10 Therefore, we hypothesize that activation of K+ channels in coronary arterial muscle contributes to hyperpolarization and vasodilation induced by different endothelium-derived vasodilators. We designed the present study to test this hypothesis by characterizing and comparing the effects of PGI2, NO, and EETs on the activity of the K+ channels in coronary vascular smooth muscle cells.
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Methods |
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Isolation of Vascular Smooth Muscle Cells From Small Coronary Arteries
Bovine hearts were obtained from a local slaughterhouse. A branch of the coronary artery was cannulated and filled with 10 to 20 mL ice-cold 3% Evan’s blue in 50 mmol/L phosphate buffer containing 0.9% sodium chloride, pH 7.4 (PSS), and 6% albumin. The heart was dissected into 2x3x1-cm pieces and sliced into 300-µm-thick tissue sections. Small coronary arteries stained with Evan’s blue were identified under a dissecting stereomicroscope. These arteries were microdissected, pooled, and stored in ice-cold PSS. The dissected small coronary arteries were first incubated for 30 minutes at 37°C with collagenase type II (340 U/mL) (Worthington), elastase (15 U/mL) (Worthington), dithiothreitol (1 mg/mL), and soybean trypsin inhibitor (1 mg/mL) in HEPES buffer consisting of (mmol/L) NaCl 119, KCl 4.7, CaCl2 0.05, MgCl2 1, glucose 5, and HEPES 10 (pH 7.4). The digested tissue was then agitated with a glass pipette to free the vascular smooth muscle cells, and the supernatant was collected. The remaining tissue was further digested with fresh enzyme solution, and the supernatant was collected at 5-minute intervals for an additional 15 minutes. The supernatants were pooled and diluted 1:10 with HEPES buffer and stored at 4°C until used.
Current Recordings
Single-channel K+ currents were recorded with the patch-clamp technique as described by Hamill et al.11 Cell-attached and inside-out configurations were used to identify the KCa and Kdrf channels. Patch pipettes were made from borosilicate glass capillaries pulled with a two-stage micropipette puller (PC-87, Sutter) and heat-polished with a microforge (MF-90, Narishige). The pipettes had tip resistances of 8 to 10 M
for single-channel recording when filled with 145 mmol/L KCl solution. Smooth muscle cells were placed in a 1-mL perfusion chamber mounted on the stage of an Nikon inverted microscope. After the tip of the pipette was positioned on a cell, a high-resistance seal (5 to 15 G) was formed between the pipette tip and the cell membrane by application of light suction. The activity of the K+ channels in the membrane spanning the pipette tip was recorded. These measurements represented the cell-attached mode. Inside-out membrane patches were excised by lifting the pipette membrane complex to the air-solution interface.
A patch-clamp amplifier (EPC-7, List Biological Laboratories, Inc) was used for recording of single-channel currents. The amplifier output signals were filtered at 1 kHz with an eight-pole Bessel filter (Frequency Devices Inc). Currents were digitized at a sampling rate of 3 kHz and stored on the hard disk of a computer (Gateway 486 DS66) for off-line analysis. Data acquisition and analysis were performed with pClamp software (version 5.7.1, Axon Instruments). Average NPo in patches was determined from recordings of several minutes by the following equation:
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Solutions
For single-channel recordings in the cell-attached mode, the bath solution contained (mmol/L) KCl 145, CaCl2 1.8, MgCl2 1.1, glucose 10, and HEPES 5 (pH 7.4) and the pipette solution contained (mmol/L) KCl 145, CaCl2 1.8, MgCl2 1.1, and HEPES 5 (pH 7.4). For single-channel recordings using the inside-out excised membrane patch, the bath solution contained (mmol/L) KCl 145, MgCl2 1.1, HEPES 10, EGTA 2, and 300 nmol/L ionized calcium (pH 7.2). For determination of the sensitivity of the channels to cytosolic Ca2+, the concentration of ionized calcium in the bath solution was varied from 10-7 to 10-6 and then to 10-5 mol/L. Calcium concentration was estimated by a computer program12 and confirmed by measurement of the free calcium concentration in the solution using fura 2 (Molecular Probes Co) with a dual wavelength spectrofluorometer (Perkin-Elmer). The pipette solution contained (mmol/L) KCl 145, CaCl2 1.8, MgCl2 1.1, and HEPES 10 (pH 7.4). All patch-clamp experiments were performed at room temperature (approximately 20°C).
Characterization of KCa and Kdrf Channels in Small Bovine Coronary Arteries
To establish current-voltage relations of the K+ channel, we exposed inside-out patches to symmetric KCl (145 mmol/L) solutions and recorded single-channel currents while we varied membrane potential from -60 to +60 mV in 20-mV steps. By changing the concentration of ionized calcium from 10-7 to 10-5 mol/L on the cytosolic side of inside-out patches, we examined the sensitivity of this KCa channel to intracellular calcium concentration. The effect of iberiotoxin (RBI), a calcium-activated K+ channel inhibitor, on single K+ channels was examined using inside-out excised membrane patches. Iberiotoxin was added to the pipette solution at a concentration of 100 nmol/L. The effect of 4-aminopyridine, a specific inhibitor of Kdrf, on single K+ channels was examined using inside-out excised membrane patches. 4-Aminopyridine (5 mmol/L) was added to the bath solution.
Effect of Endothelium-Derived Vasodilators on K+ Channel Activity
In cell-attached patches, we used symmetric KCl (145 mmol/L) solutions to null the membrane potential of the single smooth muscle cell to near 0 mV. A 3-minute control recording at a membrane potential of +40 mV was obtained after a tight seal was established. Then, the bath solution was rapidly changed by flushing the perfusion chamber with 10 mL of the same solution containing nonoate (1, 10, and 100 µmol/L; n=8), 11,12-EET (0.01, 0.1, and 1 µmol/L; n=8), or iloprost (1, 10, and 100 µmol/L; n=7), and a series of 3-minute recordings was made.
Statistics
Data are presented as mean±SE; n indicates the number of bovine hearts. We examined the significance of the differences in mean values between and within multiple groups using ANOVA for repeated measures followed by Duncan’s multiple range test. We used Student’s t test to evaluate the statistical significance of differences between two paired observations. Single-channel conductances were fit by least-squares linear regression. A value of P<.05 was considered statistically significant.
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Results |
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Characterization of K+ Currents in Small Bovine Coronary Arteries
K+ channel activity was characterized using inside-out excised membrane patches exposed to symmetric KCl solutions (145 mmol/L) to enhance single-channel conductances. Under these conditions, two types of K+ channels, one with a high-amplitude current averaging 10.3±0.1 pA and one with a low-amplitude current averaging 2.21± 0.11 pA, were detected at membrane potential of +40 mV (Fig 1A). The current-voltage relationship for both channels was linear between -60 and +60 mV, and mean slope conductance was 256.3±5 and 49.1±3 pS, respectively, with a reversal potential of approximately 0 mV (Fig 1B).
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The activity of the 256.3-pS K+ channel was enhanced when the Ca2+ concentration on the intracellular surface of the membrane was increased. At a cytosolic Ca2+ concentration of 10-7 mol/L, the NPo of this K+ channel at a membrane potential of +40 mV was 0.03±0.0012. When the cytosolic Ca2+ was increased to 10-6 or 10-5 mol/L, the NPo of this K+ channel was increased to 0.4±0.03 and 2.17±0.06, respectively. In contrast, the activity of the 49.1-pS K+ channel was not altered by changes in cytosolic Ca2+ concentration. Administration of iberiotoxin at a concentration of 100 nmol/L markedly reduced the activity of the 256.3-pS K+ channel but had no effect on the 49.1-pS K+ channels (Fig 2). In the presence of iberiotoxin (100 nmol/L), 4-aminopyridine (5 mmol/L) blocked the activity of the 49.1-pS K+ channel. 4-Aminopyridine had no effect on the 256.3-pS K+ channel. These data are consistent with the types of channels being a large conductance KCa channel and Kdrf channel, respectively.
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Effect of Nonoate on KCa and Kdrf Channel Activity
Representative recordings of single-channel K+ currents recorded in the cell-attached mode before and after addition of nonoate at a concentration of 100 µmol/L to the bath are presented in Fig 3A and 3B. Nonoate significantly increased the activity of the KCa and Kdrf channels. Fig 3C and 3D show a concentration-dependent increase in the activity of both channels induced by nonoate. The NPo of the KCa and Kdrf channels was increased 10- to 25- fold when nonoate was added to the bath at concentrations of 1 to 100 µmol/L. The effects of nonoate were blocked by 5 µmol/L oxyhemoglobin, which traps released NO (data not shown). Single-current amplitude of these channels was unaltered by nonoate even at the highest concentration studied.
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Effect of 11,12-EET on KCa and Kdrf Channel Activity
Representative recordings of single-channel K+ currents recorded in the cell-attached mode before and after addition of 11,12-EET to the bath are presented in Fig 4A and 4B. 11,12-EET significantly increased the activity of the KCa channels but did not alter the activity of the Kdrf channels. 11,12-EET at concentrations of 0.01, 0.1, and 1 µmol/L produced 0.5- to 15-fold increases in the NPo of the KCa channel (Fig 4C) but had no effect on the NPo of the Kdrf channel (Fig 4D). In some cells, the NPo of the Kdrf channel was unaltered, even when the 11,12-EET concentration was increased to 10 µmol/L. Single-current amplitude of both channels was unaltered by 11,12-EET even at the highest concentration studied (100 µmol/L).
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Effect of Iloprost on KCa and Kdrf Channel Activity
Representative recordings of single-channel K+ currents recorded in the cell-attached mode before and after addition of iloprost (100 µmol/L) to the bath are presented in Fig 5A and 5B. In contrast to 11,12-EET, iloprost significantly increased the activity of the Kdrf channels, but that of the KCa channels was unaltered. Iloprost at concentration of 1 to 100 µmol/L produced 3- to 10-fold increases in the NPo of the Kdrf channel (Fig 5D) but had no effect on the NPo of the KCa channels even at the highest concentration studied (Fig 5C). Single-current amplitude of both channels was unaltered by iloprost.
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Discussion |
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PGI2 was the first endothelium-derived vasodilator discovered.13 It is synthesized from arachidonic acid by cyclooxygenase. Recent studies have indicated that pulsatile pressure, shear stress, and a number of endogenous mediators and some drugs, such as acetylcholine, bradykinin, A23187, and thrombin, stimulate the formation and release of PGI2 from endothelial cells.1 In vitro experiments have demonstrated that PGI2 increases the concentration of cAMP in vascular smooth muscle and hence produces vasodilation.1,14 However, PGI2 has also been reported to hyperpolarize the membrane of vascular smooth muscle cells, and the hyperpolarization of smooth muscle also contributes to vasodilation.9,10 The mechanism by which PGI2 produces the hyperpolarization of vascular smooth muscle cells remains unknown. In the present study, we have found that iloprost, a stable PGI2 analogue, selectively increased the activity of the Kdrf channels, suggesting that activation of the Kdrf channels may contribute to the hyperpolarization of vascular smooth muscle induced by PGI2. Since the Kdrf channels have been reported to play an important role in the maintenance of resting membrane potential and agonist response of vascular smooth muscle,9,15 activation of the Kdrf channels may be an important mechanism by which PGI2 dilates coronary arteries. It should be noted that PGI2- or iloprost-induced hyperpolarization and relaxation of vascular smooth muscle has been reported to be blocked by inhibitors of ATP-sensitive K+ (KATP) channels in isolated mesenteric and carotid arteries.10,16 This suggests that PGI2 may relax vascular smooth muscle through KATP channel activation. However, these studies failed to characterize the effect of PGI2 on single-channel current. In smooth muscle cells of coronary arteries, we have not found typical KATP channels during single-channel recording. However, previous studies indicate that the KATP channels have biophysical properties similar to those of the Kdrf channels in this vascular bed.17–19
NO mediates the biological activity of endothelium-derived relaxing factor.20 A variety of endogenous mediators and physiological or pathological conditions, such as acetylcholine, bradykinin, A23187, thrombin, hypoxia, and wall stress, produced endothelium-dependent vasodilation through the release of NO.1–3 NO dilates vessels and increases the cGMP content of smooth muscle. Several reports failed to detect an effect of NO on membrane potential,21–23 suggesting that NO does not mediate smooth muscle hyperpolarization caused by endothelium-dependent vasodilators. Recently, several reports have argued against this view.24–26 Tare and coworkers24 have demonstrated that the hyperpolarization and relaxation evoked by acetylcholine were reduced by NG-monomethyl-L-arginine, an inhibitor of NO synthase, indicating that NO derived from the endothelium also causes the hyperpolarization of vascular smooth muscle, which may also contribute to relaxation. More recently, patch-clamp studies have shown that NO can activate the K+ channels in vascular smooth muscle cells.26 Even in cell-free membrane patches from rabbit aortic smooth muscle cells, both exogenous and native NO can directly activate single KCa channels through a mechanism that does not require cGMP.26 In the present study, we found that nonoate, an NO donor, also increases the activity of the KCa channels in coronary arterial smooth muscle cells. These results strongly support the view that NO can activate KCa channels and thus hyperpolarize vascular smooth muscle. However, our results indicated that NO is not specific to the KCa channels but also activates the Kdrf channels. The mechanism by which NO activates both KCa and Kdrf channels remains unclear. It is possible that NO can nonspecifically nitrosylate the membrane proteins of vascular smooth muscle, which activates both K+ channels. This hypothesis has yet to be tested. It has been reported that the endothelium-derived hyperpolarizing factor activates only the KCa channels27,28; therefore, the finding that NO activates both channels also indicates that it cannot represent endothelium-derived hyperpolarizing factor.
EETs are cytochrome P450 metabolites of arachidonic acid.29 Recent studies in our laboratory have indicated that the EETs are synthesized by endothelial cells and released by agonists such as methacholine.30,31 EETs hyperpolarize and relax coronary arterial smooth muscle and hence are considered as an endothelium-derived hyperpolarization factor.7,32 Patch-clamp studies have demonstrated that EETs increase the activity of the KCa channels in cerebral, renal, and coronary arterial smooth muscle cells.33–35 However, it is unknown whether EETs also alter the activities of other potassium channels. In the present study, we found that 11,12-EET had no effect on the activity of the Kdrf channels in coronary arterial smooth muscle but selectively activated the KCa channels. This finding further supports the view that EETs represent endothelium-derived hyperpolarizing factors.
In summary, we compared the effects of three major endothelium-derived vasodilators, PGI2, NO, and EETs, on the activity of the K+ channels in coronary arterial smooth muscle. The results indicate that these endothelium-derived vasodilators all alter the activity of the K+ channels in coronary arterial smooth muscle. PGI2 selectively activates the Kdrf channels, EETs selectively activate the KCa channels, and NO alters the activity of both KCa and Kdrf channels. Activation of K+ channels might contribute to the hyperpolarization and relaxation of vascular smooth muscle caused by these endothelium-derived vasodilators.
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Acknowledgments |
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This work was supported by grants from the National Heart, Lung, and Blood Institute (HL-51055) and American Heart Association, Wisconsin Affiliate (95-GB-52). The authors thank Gretchen Barg for her secretarial assistance and Phillip F. Pratt and Dr William S. Edgemond for providing the 11,12-EET.
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K. M. Gauthier, N. Spitzbarth, E. M. Edwards, and W. B. Campbell Apamin-Sensitive K+ Currents Mediate Arachidonic Acid-Induced Relaxations of Rabbit Aorta Hypertension, February 1, 2004; 43(2): 413 - 419. [Abstract] [Full Text] [PDF]
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S. I. Pomposiello, J. Quilley, M. A. Carroll, J. R. Falck, and J. C. McGiff 5,6-Epoxyeicosatrienoic Acid Mediates the Enhanced Renal Vasodilation to Arachidonic Acid in the SHR Hypertension, October 1, 2003; 42(4): 548 - 554. [Abstract] [Full Text] [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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M. Peral de Bruno, P. A. Vincent, L. Romano, D. C. Guardia, A. Coviello, and E. De Vito The novel serine protease PreR-Co promotes endothelium-independent vasorelaxation in rabbit aortic rings Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H704 - H710. [Abstract] [Full Text] [PDF]
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 K. M Gauthier, C. Liu, A. Popovic, S. Albarwani, and N. J Rusch Freshly isolated bovine coronary endothelial cells do not express the BKCa channel gene J. Physiol., December 15, 2002; 545(3): 829 - 836. [Abstract] [Full Text] [PDF]
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T. Allen, M. Iftinca, W. C Cole, and F. Plane Smooth muscle membrane potential modulates endothelium-dependent relaxation of rat basilar artery via myo-endothelial gap junctions J. Physiol., December 15, 2002; 545(3): 975 - 986. [Abstract] [Full Text] [PDF]
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M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1 J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676. [Abstract] [Full Text] [PDF]
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 X.L. Huang, D. El Kebir, A.S. De Buys Roessingh, J.C. Schneider, L. Jacob, J.C. Mercier, J. Dall'Ava-Santucci, and A.T. Dinh-Xuan Role of tyrosine phosphatase in the modulation of pulmonary vascular tone Eur. Respir. J., March 1, 2002; 19(3): 525 - 529. [Abstract] [Full Text] [PDF]
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M. Iftinca, G. J. Waldron, C. R. Triggle, and W. C. Cole State-Dependent Block of Rabbit Vascular Smooth Muscle Delayed Rectifier and Kv1.5 Channels by Inhibitors of Cytochrome P450-Dependent Enzymes J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 718 - 728. [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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P. F. Pratt, P. Li, C. J. Hillard, J. Kurian, and W. B. Campbell Endothelium-independent, ouabain-sensitive relaxation of bovine coronary arteries by EETs Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1113 - H1121. [Abstract] [Full Text] [PDF]
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S. I. Pomposiello, M. A. Carroll, J. R. Falck, and J. C. McGiff Epoxyeicosatrienoic Acid-Mediated Renal Vasodilation to Arachidonic Acid Is Enhanced in SHR Hypertension, March 1, 2001; 37(3): 887 - 893. [Abstract] [Full Text] [PDF]
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 M. Fukao, H. S. Mason, J. L. Kenyon, B. Horowitz, and K. D. Keef Regulation of BKca Channels Expressed in Human Embryonic Kidney 293 Cells by Epoxyeicosatrienoic Acid Mol. Pharmacol., January 1, 2001; 59(1): 16 - 23. [Abstract] [Full Text]
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 M. Hecker Endothelium-Derived Hyperpolarizing Factor--Fact or Fiction? Physiology, February 1, 2000; 15(1): 1 - 5. [Abstract] [Full Text] [PDF]
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Y. Nishikawa, D. W. Stepp, and W. M. Chilian In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1252 - H1259. [Abstract] [Full Text] [PDF]
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P.-L. Li, C.-L. Chen, R. Bortell, and W. B. Campbell 11,12-Epoxyeicosatrienoic Acid Stimulates Endogenous Mono-ADP-Ribosylation in Bovine Coronary Arterial Smooth Muscle Circ. Res., August 20, 1999; 85(4): 349 - 356. [Abstract] [Full Text] [PDF]
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H.-C. Lee, T. Lu, N. L Weintraub, M. VanRollins, A. A Spector, and E. F Shibata Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes J. Physiol., August 15, 1999; 519(1): 153 - 168. [Abstract] [Full Text] [PDF]
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R. Laporte and I. Laher Sarcoplasmic reticulum and endothelium independently regulate venous smooth muscle [Ca2+]i and contraction Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H749 - H755. [Abstract] [Full Text] [PDF]
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 H. Miura, Y. Liu, and D. D. Gutterman Human Coronary Arteriolar Dilation to Bradykinin Depends on Membrane Hyperpolarization : Contribution of Nitric Oxide and Ca2+-Activated K+ Channels Circulation, June 22, 1999; 99(24): 3132 - 3138. [Abstract] [Full Text] [PDF]
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I. R. Hutcheson, A. T. Chaytor, W. H. Evans, and T. M. Griffith Nitric Oxide–Independent Relaxations to Acetylcholine and A23187 Involve Different Routes of Heterocellular Communication : Role of Gap Junctions and Phospholipase A2 Circ. Res., January 22, 1999; 84(1): 53 - 63. [Abstract] [Full Text] [PDF]
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J. D. Imig, E. W. Inscho, P. C. Deichmann, K. M. Reddy, and J. R. Falck Afferent Arteriolar Vasodilation to the Sulfonimide Analog of 11,12-Epoxyeicosatrienoic Acid Involves Protein Kinase A Hypertension, January 1, 1999; 33(1): 408 - 413. [Abstract] [Full Text] [PDF]
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C.-W. Sun, M. Alonso-Galicia, M. R. Taheri, J. R. Falck, D. R. Harder, and R. J. Roman Nitric Oxide-20–Hydroxyeicosatetraenoic Acid Interaction in the Regulation of K+ Channel Activity and Vascular Tone in Renal Arterioles Circ. Res., November 30, 1998; 83(11): 1069 - 1079. [Abstract] [Full Text] [PDF]
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 D. Salvail, M. Dumoulin, and E. Rousseau Direct modulation of tracheal Cl--channel activity by 5,6- and 11,12-EET Am J Physiol Lung Cell Mol Physiol, September 1, 1998; 275(3): L432 - L441. [Abstract] [Full Text] [PDF]
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P.-L. Li, A.-P. Zou, and W. B. Campbell Regulation of KCa-channel activity by cyclic ADP-ribose and ADP-ribose in coronary arterial smooth muscle Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H1002 - H1010. [Abstract] [Full Text] [PDF]
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P.-L. Li, M.-W. Jin, and W. B. Campbell Effect of Selective Inhibition of Soluble Guanylyl Cyclase on the KCa Channel Activity in Coronary Artery Smooth Muscle Hypertension, January 1, 1998; 31(1): 303 - 308. [Abstract] [Full Text] [PDF]
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K. M. Gauthier-Rein and N. J. Rusch Distinct Endothelial Impairment in Coronary Microvessels from Hypertensive Dahl Rats Hypertension, January 1, 1998; 31(1): 328 - 334. [Abstract] [Full Text] [PDF]
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W. B. Campbell, C. Deeter, K. M. Gauthier, R. H. Ingraham, J. R. Falck, and P.-L. Li 14,15-Dihydroxyeicosatrienoic acid relaxes bovine coronary arteries by activation of KCa channels Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1656 - H1664. [Abstract] [Full Text] [PDF]
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P.-L. Li, D. X. Zhang, Z.-D. Ge, and W. B. Campbell Role of ADP-ribose in 11,12-EET-induced activation of KCa channels in coronary arterial smooth muscle cells Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1229 - H1236. [Abstract] [Full Text] [PDF]
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