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Right arrow Cardiac - pharmacology

Ann Thorac Surg 2001;72:1970-1976
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Epoxyeicosatrienoic acids (EET11,12) may partially restore endothelium-derived hyperpolarizing factor–mediated function in coronary microarteries

Wei Zou, MDa, Qin Yang, MDa, Anthony P.C. Yim, MDa, Guo-Wei He, MD, PhD*a,b

a Cardiovascular Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
b Cardiovascular Research, Providence Heart Institute & Starr Academic Center, Providence St. Vincent Hospital, Portland, Oregon, USA

Accepted for publication July 16, 2001.

* Address reprint requests to Dr He, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
e-mail: gwhe{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Endothelial cells derive nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The cytochrome P-450–monooxygenase metabolites of arachidonic acid (epoxyeicosatrienoic acids [EETs]) have been suggested to be EDHF. This study was designed to examine the effect of EET11,12 with regard to the possibility of restoring EDHF function when added into hyperkalemic cardioplegic solution.

Methods. Porcine coronary microartery rings were studied in a myograph. In groups 1 and 2, paired arteries were incubated in either hyperkalemic solution (K+ 20 mmol/L) or Krebs’ solution (control). In group 3, the paired arteries were incubated in hyperkalemia plus EET11,12 (1 x 10-6.5 mol/L) or hyperkalemia alone (control) at 37°C for 1 hour, followed by Krebs’ washout and then precontracted with 1 x 10-8.5 mol/L U46619. The EDHF-mediated relaxation to EET11,12 (group 1) or bradykinin (groups 2 and 3) was studied in the presence of NG-nitro-L-arginine, indomethacin, and oxyhemoglobin.

Results. After exposure to hyperkalemia, the EDHF-mediated maximal relaxation by bradykinin (72.5% ± 7.8% versus 41.6% ± 10.6%; p < 0.05), but not by EET11,12 (18.4% ± 3.3% versus 25.1% ± 4.9%; p > 0.05) was significantly reduced. Incubation with EET11,12 partially restored EDHF function (33.3% ± 9.5% versus 62.0% ± 8.5%; p < 0.05).

Conclusions. In coronary microarteries, hyperkalemia impairs EDHF-mediated relaxation, and EET11,12 may partially mimic the EDHF function. Addition of EET11,12 into cardioplegic solution may partially restore EDHF-mediated function reduced by exposure to hyperkalemia.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Owing to the wide use of hyperkalemic cardioplegic and organ preservation solutions in cardiac and transplantation operations, the effect of such solutions on endothelial function has been the focus of several recent studies. Vascular endothelium plays a key role in the regulation of vascular tone through releasing diverse vasodilator substances [1–4]. Among these, endothelium-derived relaxing factors (EDRFs) are responsible for endothelium-dependent relaxation [4]. The major components of EDRFs have been shown to be endothelium-derived nitric oxide (NO) [5, 6], prostacyclin (PGI2) [7], and endothelium-derived hyperpolarizing factor (EDHF) [8–10]. Although the activity of EDHF has been demonstrated in arteries from various species, the chemical nature of EDHF has not been finally identified [9–11]. Most recently, the cytochrome P-450 monooxygenase metabolites of arachidonic acid, possibly endogenous cannabinoids (epoxyeicosatrienoic acids [EETs]), have been suggested to be EDHF [12–16]. Epoxyeicosatrienoic acids are vasodilators, especially of smaller, more peripheral vessels such as intestinal microvessels and caudal, cerebral, renal, and coronary arteries, as well as resistance arterioles of the kidney [17–20]. Epoxyeicosatrienoic acids hyperpolarize vascular smooth muscle by increasing the open probability of calcium-activated potassium channels. Studies also show that EDHF may back up or enhance the relaxing action of NO, particularly when the NO-mediated relaxation is impaired, as seen in some pathologic states such as hypercholesterolemia, hypertension, and diabetes mellitus [21].

During cardiac operation, injury to the heart involves (1) ischemia-reperfusion injury to the myocytes and coronary circulation and (2) possible injury to the coronary circulation by cardioplegic solution because of its hyperkalemic components. We have previously demonstrated that EDHF-mediated function in both large and microcoronary arteries is reduced by hyperkalemic solutions such as St. Thomas’ cardioplegia [1, 2, 22–25] and the University of Wisconsin solution [21].

Previous findings suggested that the mechanism of EDHF is related to EET [17–20]. In fact, there are many similar properties between EDHF and EETs. For example, both EETs and EDHF can be synthesized by vascular endothelial cells, are released by the endothelium in response to endothelium-dependent vasodilators, and can relax vascular smooth muscle and increase the open probabilities of calcium-activated potassium channels in cell-attached patches [15]. We have previously demonstrated that EDHF-mediated relaxation is impaired when coronary arteries are exposed to hyperkalemia [21–25]. It has not been studied whether EETs (particularly EET11,12) mimic EDHF function in the coronary artery and whether addition of EET11,12 may restore EDHF-mediated function reduced by exposure to hyperkalemia.

The present study was designed to examine the effect of EET11,12 on mimicking EDHF-mediated relaxation in the coronary microartery during exposure to hyperkalemic cardioplegic solution.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Microarterial preparation and mounting
Fresh porcine hearts collected from a local slaughterhouse were placed in a container filled with cold Krebs’ solution and immediately transferred to the laboratory. On receipt of the heart, intramyocardial microcoronary arteries (usually the tertiary branches of the left anterior descending coronary artery) were carefully dissected and removed to protect the endothelium. The vessels were cleaned of fat and connective tissue and cut into cylindrical rings of 2 mm (for intramyocardial arteries) length under a microscope. The Krebs’ solution was aerated with a gas mixture of 95% oxygen and 5% carbon dioxide at 37°C and had the following composition (in mmol/L): Na+, 144; K+, 5.9; Ca2+, 2.5; Mg2+, 1.2; Cl-, 128.7; HCO3, 25; SO42-, 1.2; H2PO4-, 1.2; glucose, 11.0.

Normalization
A microarterial ring was guided onto a suitable length of two stainless-steel wires (40 mm in diameter) through its lumen under microscope. One wire was fixed tightly on a jaw in a two-channel Mulvany myograph and the other on the other jaw of the same chamber. These two wires were attached to a force transducer or to a micrometer, respectively. A previously described method [2, 26–28] was used to normalize vascular rings under a condition simulating the transmural pressure in vivo encountered by the coronary microartery. Briefly, the artery rings were progressively stretched until the passive transmural pressure reached 100 mm Hg. The internal circumference was then set to a normalized value, estimated to be equivalent to 90% of the circumference at a passive transmural pressure of 100 mm Hg.

Protocol
After the normalization procedure, rings were equilibrated at for least 40 minutes.

Precontraction
The vessel was contracted with thromboxane A2 mimetic U46619 (1 x 10-8.5 mol/L). This dose was chosen according to our previous studies in porcine coronary arteries [3]. U46619 at 1 x 10-8.5 mol/L caused a stable submaximal contraction of all rings.

Endothelium-derived hyperpolarizing factor–mediated (indomethacin, ng-nitro-l-arginine, and oxyhemoglobin resistant) relaxation
With the presence of the specific inhibitor for cyclooxygenase, indomethacin (Indo, 7 mmol/L), the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 300 mmol/L), and the NO scavenger, oxyhemoglobin (HbO, 20 mmol/L), concentration-relaxation curves to EET11,12 (1 x 10-10 to 1 x 10-6.5 mol/L, group 1) and bradykinin (BK, 1 x 10-10 to 1 x 10-6.5 mol/L, groups 2 and 3) were established when the U46619-induced contraction reached a plateau. Bradykinin is known to induce endothelium-dependent relaxation through all three pathways—NO, PGI2, and EDHF. In the present study, the relaxation is mediated by EDHF because the production of NO and PGI2 is abolished by the above inhibitors and scavengers [23].

Epoxyeicosatrienoic acid11,12–mediated relaxation after exposure to hyperkalemia
Group 1
After normalization, rings were equilibrated for 40 minutes. One ring was then incubated with hyperkalemia (K+ 20 mmol/L, n = 14) for 1 hour and the other with Krebs’ solution as control (n = 14). The rings were then repeatedly washed with Krebs’ solution and incubated with Indo (7 µmol/L), L-NNA (300 µmol/L), and HbO (20 µmol/L) for 30 minutes, before the U46619 (1 x 10-8.5 mol/L)-induced precontraction. Cumulative concentration-relaxation curves to EET11,12 (1 x 10-10 to 1 x 10-6.5 mol/L) were established.

In the hyperkalemic solution, K+ 20 mmol/L was used to replace the equivalent Na+ in the Krebs’ solution.

Effect of incubation with epoxyeicosatrienoic acid11,12 on bradykinin-induced, endothelium-derived hyperpolarizing factor–mediated relaxation
Group 2. Effect of hyperkalemia on bradykinin-induced, endothelium-derived hyperpolarizing factor–mediated relaxation
After normalization, the rings were equilibrated for 40 minutes. One ring was then incubated with hyperkalemia (K+ 20 mmol/L, n = 8) for 1 hour and the other with Krebs’ solution as control (n = 8). The rings were then repeatedly washed with Krebs’ solution and incubated with Indo (7 µmol/L), L-NNA (300 µmol/L), and HbO (20 µmol/L) for 30 minutes.

The rings were precontracted with U46619 (1 x 10-8.5 mol/L) and cumulative concentration-relaxation curves to BK (1 x 10-10 to 1 x 10-6.5 mol/L) were established.

Group 3. Effect of incubation with hyperkalemia plus epoxyeicosatrienoic acid11,12 on bradykinin-induced, endothelium-derived hyperpolarizing factor–mediated relaxation
After normalization, the rings were equilibrated for 40 minutes. One ring was then incubated with hyperkalemia (K+ 20 mmol/L) plus EET11,12 (1 x 10-6.5 mol/L, n = 9) for 1 hour and the other ring was incubated with hyperkalemia (K+ 20 mmol/L, n = 9) as control. The rings were then repeatedly washed with Krebs’ solution and incubated with Indo (7 µmol/L), L-NNA (300 µmol/L), and HbO (20 µmol/L) for 30 minutes.

The rings were then precontracted with U46619 (1 x 10-8.5 mol/L) and cumulative concentration-relaxation curves to BK (1 x 10-10 to 1 x 10-6.5 mol/L) were established.

In all experiments, the washout time (the time between the start of washout and the start of the concentration-relaxation curve to EET11,12 or BK) was controlled within 45 minutes [3]. Only one concentration-relaxation curve was obtained from each coronary ring. A mean concentration-relaxation curve was established from 8 to 14 rings in each group of experiment. During the experiment, the hyperkalemia or Krebs’ solution in the myograph chambers was continuously bubbled with a gas mixture of 95% oxygen and 5% carbon dioxide.

Data analysis
Mean maximal relaxation for each group was calculated from the maximal relaxation of different rings induced by BK. The effective concentration of the relaxing agent that caused 50% of the maximal relaxation was defined as EC50.

The EC50 was determined from each concentration-relaxation curve by a logistic, curve-fitting equation [24], as follows:

where E is response, M is maximal relaxation, A is concentration, K is EC50 concentration, and P is the slope parameter.

Statistical analysis
All statistical analyses were performed with SPSS software (SPSS, Inc, Chicago, IL). The significance of the difference between mean values was calculated by the paired or unpaired Student’s t test when appropriate. Results are expressed as mean ± standard error of the mean for n observations, where n equals the number of coronary arterial rings.

Drugs
Chemicals used and their sources were as follows: BK, L-NNA, Indo, HbO, and EET11,12 (Sigma Chemical Co, St. Louis, MO); U46619 (Cayman Chemical, Ann Arbor, MI). Solutions of L-NNA (dissolved in distilled water) and Indo (dissolved in ethanol) were stored at 4°C. Solutions of U46619, HbO, BK, and EET11,12 were held frozen until required.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Resting force
There were no significant differences among the arteries exposed to hyperkalemia and Krebs’ solution or hyperkalemia plus EET11,12 with regard to the resting force (p > 0.5). Table 1 gives the detail of the resting force in these microarteries.


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  		Table 1. Resting Force in Coronary Microarteriesa

 
Oxyhemoglobin-induced contraction force
In all coronary arterial rings, HbO (20 mmol/L) induced a rapid and significant increase in the basal tone of coronary rings in all groups. It was 1.8 ± 0.4 mN versus 2.2 ± 0.4 mN in control rings in group 1 (n = 14; 95% confidence interval [CI], -1.56 to 0.75 mN; p = 0.7), 1.0 ± 0.3 mN versus 1.7 ± 0.5 mN in control rings in group 2 (n = 8; 95% CI, -2.0 to 0.5 mN; p = 0.03), and 1.8 ± 0.4 mN versus 1.9 ± 0.5 mN in control rings in group 3 (n = 9; 95% CI, -1.5 to 1.3 mN; p = 0.4).

U46619-induced contraction force
In all coronary arterial rings, U46619 (1 x 10-8.5 mol/L) induced a stable and rapidly developed tension. This contraction force was reduced by exposure to hyperkalemia when measured at washout for 45 minutes (4.7 ± 0.6 mN versus 4.9 ± 0.4 mN in control rings in group 1, n = 14; 95% CI, -1.62 to 1.18 mN; p = 0.3; 3.0 ± 0.7 mN versus 2.7 ± 0.6 mN in control rings in group 2, n = 8; 95% CI, -1.68 to 2.38 mN; p = 0.1; 5.3 ± 0.6 mN versus 6.2 ± 0.7 mN in control rings in group 3, n = 9; 95% CI, -2.95 to 1.06 mN; p = 0.8).

Epoxyeicosatrienoic acid11,12–induced relaxation in coronary microarteries after exposure to hyperkalemia
Group 1
In the control rings in the presence of Indo (7 µmol/L/L), L-NNA (300 µmol/L/L), and HbO (20 µmol/L/L) in Krebs’ solution, EET11,12 induced a maximal relaxation of 18.4% ± 3.3% with an EC50 of 1 x 10-8.30 ± 1 x 10-0.83 mol/L (Fig 1, Table 2). Treatment alone with hyperkalemia for 1 hour followed by washout for 45 minutes did not significantly alter the EET11,12-induced maximal relaxation to 25.1% ± 4.9% (n = 14; 95% CI, 5.5% to 18.9%; p = 0.5; Fig 1) with EC50 of 1 x 10-8.01 ± 1 x 10-0.62 mol/L.



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  		Fig 1. Relaxation of porcine coronary microartery rings precontracted with 1 x 10-8.5 mol/L U46619 in response to epoxyeicosatrienoic acid11,12 (EET11,12) in the presence of 7 µmol/L indomethacin (I), 300 µmol/L NG-nitro-L-arginine (L), and 20 µmol/L oxyhemoglobin (Hb) at 45 minutes of washout after exposure to hyperkalemia (K+20) or Krebs’ solution (Control) at 37°C for 1 hour. Two artery rings were taken from the same artery and allocated into the paired groups. (A) Mean concentration (negative log moles per liter)-relaxation (percent of contraction by U46619) curves for EET11,12 are shown. Vertical error bars are one standard error of the mean; p > 0.05 at all concentrations (n = 14, unpaired Student’s t test). (B) Digitized traces of original chart recordings from two rings taken from the same artery, showing the changes in isometric tension under the conditions indicated on the tracings.

 

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  		Table 2. Maximal Relaxation and Effective Concentration Producing 50% Relaxation for Bradykinin and Epoxyeicosatrienoic Acid11,12 in the Presence of Indomethacin (7 µmol/L), NG-Nitro-L-Arginine (300 µmol/L) and Oxyhemoglobin (20 µmol/L)a

 
Bradykinin-induced relaxation
Group 2
In the control rings in the presence of Indo (7 µmol/L/L), L-NNA (300 µmol/L/L), and HbO (20 µmol/L/L) in Krebs’ solution, BK induced a maximal relaxation of 72.5% ± 7.8% with an EC50 of 1 x 10-7.30 ± 1 x 10-0.89 mol/L (Fig 2). Treatment with hyperkalemia for 1 hour followed by washout for 45 minutes significantly reduced BK-induced maximal relaxation to 41.6% ± 10.6% (n = 8; 95% CI, 58.9% to 3%; p = 0.03; Fig 2) with EC50 of 1 x 10-6.35 ± 1 x 10-0.70 mol/L.



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  		Fig 2. Relaxation of porcine coronary microartery rings precontracted with 1 x 10-8.5 mol/L U46619 in response to bradykinin (BK) in the presence of 7 µmol/L indomethacin (I), 300 µmol/L NG-nitro-L-arginine (L), and 20 µmol/L oxyhemoglobin (Hb) at 45 minutes of washout after exposure to hyperkalemia (K+20) or Krebs’ solution (Control) at 37°C for 1 hour. Two artery rings were taken from the same artery and allocated into the paired groups. (A) Mean concentration (negative log moles per liter)-relaxation (percent of contraction by U46619) curves for bradykinin are shown. Vertical error bars are one standard error of the mean; *p = 0.03 (n = 8; unpaired Student’s t test). (B) Digitized traces of original chart recordings from two rings taken from the same artery, showing the changes in isometric tension under the conditions indicated on the tracings.

 
Group 3
In the presence of Indo (7 µmol/L/L), L-NNA (300 µmol/L/L), and HbO (20 µmol/L/L), in rings incubated with hyperkalemia at 37°C for 1 hour followed by washout for 45 minutes, the BK-induced maximal relaxation was significantly reduced to 33.3% ± 9.5% (n = 9; 95% CI, 1.6% to 5.57%; p = 0.039; Fig 3) with an EC50 of 1 x 10-7.66 ± 1 x 10-0.74 mol/L, whereas in the rings incubated in hyperkalemia plus EET11,12, BK induced a maximal relaxation of 62.0% ± 8.5% with an EC50 of 1 x 10-7.27 ± 1 x 10-0.49 mol/L (Fig 3).



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  		Fig 3. Relaxation of porcine coronary microartery rings precontracted with 1 x 10-8.5 mol/L U46619 in response to bradykinin (BK) in the presence of 7 µmol/L indomethacin (I), 300 µmol/L NG-nitro-L-arginine (L), and 20 µmol/L oxyhemoglobin (Hb) at 45 minutes of washout after exposure to hyperkalemia (K+20) plus epoxyeicosatrienoic acid11,12 (EET11,12; 0.3 µmol/L) or hyperkalemia (Control) at 37°C for 1 hour. Two artery rings were taken from the same artery and allocated into the paired groups. (A) Mean concentration (negative log moles per liter)-relaxation (percent of contraction by U46619) curves for EET11,12 are shown. Vertical error bars are one standard error of the mean; *p = 0.04 (n = 9; unpaired Student’s t test). (B) Digitized traces of original chart recordings from two rings taken from the same artery, showing the changes in isometric tension under the conditions indicated on the tracings.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present study demonstrates that (1) although EET11,12 may not be identical to EDHF in porcine coronary microarteries, it may partially mimic the effect of EDHF; and (2) when added to hyperkalemic solution (K+ 20 mmol/L), EET11,12 may partially restore the EDHF-mediated (Indo, L-NNA, and HbO resistant), endothelium-dependent relaxation in the coronary microartery.

Endothelium-derived hyperpolarizing factor plays an important role in coronary microarteries
As described earlier, the nature of EDHF has not been finally identified [4–7, 11]. Several candidates for EDHF have been proposed. These include EETs, the cytochrome P-450 monooxygenase metabolite of arachidonic acid, K+, anandamide, NO, PGI2, adenosine triphosphate, ammonia, and citrulline [11, 29]. Nitric oxide relaxes blood vessels by activating soluble guanylate cyclase in smooth muscle cells and by opening potassium channels to hyperpolarize underlying vascular smooth muscle cells. Prostacyclin is formed by the action of prostacyclin synthase on endoperoxides, which are produced by cyclooxygenase. It increases the level of cyclic adenosine monophosphate by activating adenylate cyclase to evoke vasorelaxation [30]. In contrast, EDHF elicits relaxation of blood vessels by opening potassium channels on the smooth muscle cell membrane and subsequent hyperpolarization [31, 32]. Although EDHF has been reported to play a role in large-conductance coronary arteries [12, 14, 20, 33], it plays an even more important role in the regulation of vascular tone in the microcirculation than in the large-conductance arteries [2, 3, 34, 35]. The present study also demonstrates this because in the presence of inhibitors of NO and PGI2, BK induced as much as 72.5% of relaxation. This is in accordance with our previous observations in the coronary microarteries [2, 3, 34, 35].

Endothelium-derived hyperpolarizing factor–mediated (indomethacin, NG-nitro--arginine, and oxyhemoglobin resistant) relaxation in the coronary microarteries
The endothelium derives at least three relaxing factors (NO, PGI2, and EDHF). When PGI2 and NO are blocked by Indo and L-NNA, respectively, the residual relaxation is thought to be caused by EDHF. However, by direct measurement of NO we have demonstrated that NO production cannot be abolished by L-NNA [35]. However, further addition of HbO scavenges the residual NO and under such conditions, the residual relaxation is caused by EDHF [35]. Therefore, in the present study, all experiments were performed in the presence of the inhibitors of NO and PGI2 (L-NNA and Indo), as well as the scavenger of NO (HbO), to ensure that the residual relaxation is truly caused by EDHF. We also demonstrated that this relaxation is linked with a membrane hyperpolarization in coronary conductance arteries [33] and in microarteries [2, 34, 35]. In the present study, the EDHF stimulus BK induced 72.5% relaxation of the U46619-induced precontraction. Taken together with our previous electrophysiologic studies in the coronary arteries [3, 33, 35], this relaxation is obviously the effect of EDHF.

Epoxyeicosatrienoic acid11,12 may partially mimic the endothelium-derived hyperpolarizing factor–mediated relaxation in the porcine coronary microartery
Epoxyeicosatrienoic acids have been described as EDHF, because these substances have many of the known properties of EDHF, as described earlier. In the present study, in the presence of Indo (7 µmol/L/L), L-NNA (300 µmol/L/L), and HbO (20 µmol/L/L), EET11,12 induced a maximal relaxation of only 18.4% ± 3.3%, compared with 72.5% induced by BK. The result does not support the concept that in the porcine coronary microarteries, EDHF is an EET, although it is possible that EETs may partially mimic the effect of EDHF.

Effect of epoxyeicosatrienoic acid11,12 added in hyperkalemia may partially restore the endothelium-derived hyperpolarizing factor–mediated relaxation in the porcine coronary microarteries
In the porcine coronary microartery, treatment alone with hyperkalemic solution (K+ 20 mmol/L) at 37°C for 1 hour significantly reduced the BK-induced maximal relaxation. This is in accordance with our published data [2, 3, 21, 24, 25, 33, 34]. This reduced relaxation (41.6%) was able to be restored to 62.0% by adding EET11,12 in the hyperkalemic solution during incubation. This result provides a useful clinical approach for improvement of depolarizing (hyperkalemic) cardioplegic solution.

Hyperkalemic cardioplegic solution reduces EDHF-mediated coronary endothelial function, and this may be related to diminished coronary perfusion during the reperfusion period. The diminished endothelial function mediated by EDHF may be at least partially restored by adding EDHF mimics such as EETs in the cardioplegic solution, and this may be a new clinical approach to further improve the effectiveness of depolarizing cardioplegic solutions.

In conclusion, the present study suggests that although EET11,12 may not be identical to EDHF in porcine coronary microarteries, it may partially mimic EDHF function in these arteries. Addition of EET11,12 into hyperkalemic cardioplegic solution may partially restore EDHF-mediated function reduced by exposure to hyperkalemia. Further study is necessary to clarify whether this is also true in the clinical setting. [36, 37]


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was fully supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project Nos. CUHK7246/99M and CUHK4127/01M), China, and the Providence St. Vincent Medical Foundation, Portland, OR.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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