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Right arrow Cardiac - pharmacology

Ann Thorac Surg 2005;79:2065-2071
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Release of Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor (EDHF) in Porcine Coronary Arteries Exposed to Hyperkalemia: Effect of Nicorandil

Qin Yang, MD, PhDa, Rong-Zhen Zhang, MD, PhDa, Anthony P.C. Yim, MDa, Guo-Wei He, MD, PhD, DSca,b,c,*

a Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
b Starr Academic Center, Providence Heart Institute, Department of Surgery, Oregon Health and Science University, Portland, Oregon
c Wuhan Heart Institute, The Central Hospital of Wuhan, Wuhan, China

Accepted for publication November 17, 2004.

Abbreviations and acronyms ANOVA = analysis of variance; EC50 = 50% effective concentration; EDHF = endothelium-derived hyperpolarizing factor; EDRF = endothelium-derived relaxing factors; Hb = hemoglobin; NO = nitric oxide; L-NNA = NG-nitro-L-arginine; HbO = oxyhemoglobin; K+ = potassium; PGI2 = prostacyclin

* Address reprint requests to Prof He, Department of Surgery, Block B, 5A, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China (E-mail: gwhe{at}cuhk.edu.hk).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Although the detrimental effect of hyperkalemia on coronary endothelium has been reported, there is no direct evidence regarding the effect of hyperkalemic exposure on nitric oxide (NO) release from the coronary endothelium. In addition, it is unclear whether nicorandil, a KATP channel opener, used as hyperpolarizing cardioplegia or added in hyperkalemic cardioplegic solution may protect endothelial function during cardiac surgery. The present study was designed to clarify NO release and the function of endothelium-derived hyperpolarizing factor (EDHF) in coronary circulation with respect to the effect of hyperkalemia and nicorandil.

METHODS: Nitric oxide was measured by using a NO-specific electrode, and EDHF-mediated relaxation was investigated in a myograph. Substance P- and calcium ionophore A23187-induced NO release was compared in porcine left circumflex coronary arteries before and after 1-hour exposure to 20 mM potassium (K+) at 37°C. In coronary microarteries (diameter 200 to 450 µm), precontracted with U46619, in the presence of indomethacin (7 µM), NG-nitro-L-arginine (300 µM), and oxyhemoglobin (20 µM), EDHF-mediated relaxation was induced by bradykinin (–10 to –6.5 log M) after incubation with Krebs (control) or 20 mM K+ with or without 10 µM nicorandil at 37°C for 1 hour.

RESULTS: Neither substance P (58.8 ± 5.0 versus 66.2 ± 7.2 nmol/L) nor A23187 (86.6 ± 9.0 versus 82.4 ± 9.2 nmol/L in control) induced NO release was altered by hyperkalemic exposure (p > 0.05). In contrast, EDHF-mediated relaxation was decreased from 84.2% ± 3.8% to 42.3% ± 6.0% (p < 0.001) that was partially restored by nicorandil (50.7% ± 5.5%, p < 0.05).

CONCLUSIONS: Exposure to potassium at 20 mM does not affect NO release but impairs EDHF-mediated relaxation in coronary arteries. Supplementation of nicorandil in hyperkalemic cardioplegia may provide a protective effect on EDHF-related endothelial function.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Hyperkalemic cardioplegia has been widely used in cardiac surgery. As a major ion component, potassium (K+) at high concentrations (hyperkalemia) induces immediate cardiac arrest, which lowers energy demand and conserves the myocardial energy reserves. This energy preservation ultimately leads the heart to better tolerance to ischemia during the operation [1, 2].

Although the general strategy of myocardial protection in cardiac surgery is still using hyperkalemia in either blood or crystalloid cardioplegia, a number of studies in the last decades have indicated the unfavorable effect of hyperkalemic solutions on vascular endothelial function [3–5].

The endothelial damage due to hyperkalemia has been reported to be associated with altered vascular resistance, blood flow, and vasodilatation [3–5]. Investigations from our laboratory on individual endothelium-derived relaxing factors (EDRFs) demonstrated the susceptibility of endothelium-derived hyperpolarizing factor (EDHF) to high concentrations of K+ [6–9]. In contrast, although there are a number of studies [3–5] that reported the effect of hyperkalemia on the endothelial function as a whole, the direct effect of hyperkalemia on the release of nitric oxide (NO), the other major EDRF, has not been reported. Therefore, the first objective of the present study was to investigate the effect of the high concentration of K+ used in cardioplegia on the endothelium-derived NO release. A direct and sensitive method—electrochemical measurement of the NO concentration—was used.

Further, because the coronary endothelium largely contributes to the entire cardiac performance, how to protect the function of endothelium, in addition to myocardium, has attracted great attention among cardiac surgeons. Supplementation with a K+ channel opener, such as aprikalim, in hyperkalemic cardioplegia, not only improves ventricular contractility but also preserves EDHF-mediated coronary relaxation [10, 11]. Nicorandil is a hybrid K+ channel opener that also possesses NO-release property. Use of nicorandil shows potent cardioprotective effect in rabbits [12]. When nicorandil is used as a component of St. Thomas Hospital [13] or blood [14] cardioplegia, replacing potassium, it improves preservation of energetics and function in pig hearts. It has been also reported that when added in cold hyperkalemic solution, nicorandil is beneficial to the indomethacin and NG-nitro-L-arginine-resistant endothelial function in the pig [15]. More importantly, nicorandil is the only K+ channel opener used clinically as cardioplegia to protect the myocardial function, and a recent clinical study in coronary surgery by Hayashi and colleagues [16] suggests that nicorandil administration during cardiopulmonary bypass provides enhanced myocardial protective effects against ischemia-reperfusion in patients undergoing coronary artery bypass grafting.

With the recognition that coronary microcirculation is crucial for myocardial perfusion, the second part of the present study was designed to investigate the effect of nicorandil on endothelial function in porcine coronary microarteries with regard to EDHF. This objective was fulfilled by evaluating the effect of nicorandil and the effect of nicorandil as an additive to hyperkalemic solution.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
General
Fresh porcine hearts collected from a local slaughterhouse were placed in a container filled with cold Krebs solution and immediately transferred to the laboratory. Upon receipt of the heart, left circumflex coronary arteries (for NO measurement) and intramyocardial coronary microarteries, usually the tertiary branches of the left anterior descending artery, with diameter ranging from 200 to 450 µm (for isometric force study) were carefully dissected out with great caution to protect the endothelium. The Krebs solution was preaerated with a gas mixture of 95% O2 to 5% CO2 at 37°C and had the following composition (in mM): 144 Na+, 5.9 K+, 2.5 Ca2+, 1.2 Mg2+, 128.7 Cl-, 25 HCO3-, 1.2 SO42-, 1.2 H2PO4-, and 11.0 glucose.

NO Measurement
Nitric oxide was directly measured electrochemically. A membrane-type NO-sensitive electrode (ISO-NOP; World Precision Instrument, Sarasota, FL) and isolated NO meter (ISO-NO Mark II; World Precision Instrument) were used to measure the NO generated by vascular endothelium as in our previous studies in both animal and human vessels [17–20]. The detection of NO is an electrochemical method in which a potential is applied to the measuring electrode relative to the reference electrode, and the resulting current due to the electrochemical oxidation of NO is monitored. The membrane-type NO sensitive electrode consists of a working electrode covered by a gas-permeable polymeric membrane. The NO diffuses through the selective membrane or coatings and is oxidized on the surface of the prepolarized electrode, resulting in an electrical current. The magnitude of the redox current is in direct proportion to the concentration of NO in the sample and is amplified by the NO meter and registered by a computer (Duo·18 data recording system; World Precision Instrument). The ISO-NOP has an inherently high selectivity due to its electrodes being separated from the sample in which measurements are being made by gas-permeable hydrophobic membranes. This excludes interference from solution or dissolved species other than gas [7–20].

The selectivity of the NO-sensitive electrode was tested in connection with calibration, where a lack of response to strong saline solution (3 moles/L) or sodium nitrite up to 100 µmol/L was taken as evidence for an intact coating of the electrode. The electrodes did not respond to acetylcholine (10 µmol/L), bradykinin (1 µmol/L), indomethacin (7 µmol/L), NG-nitro-L-arginine (L-NNA, 300 µmol/L), and oxyhemoglobin (HbO, 20 µmol/L) that were added into the calibration glass vial.

The membrane-type electrode is calibrated by chemical titration based on the following equation:


{4022969.2065.si1}

(1)
where a known amount of KNO2 is added to produce a known amount of NO. The quantity (and so the concentration) of NO generated can be calculated directly from the stoichiometry if the concentrations of the reagents are known [19, 20].

The calibration was performed daily before the experiment. The NO-sensitive electrode was inserted into the organ chamber vertically and placed as close to the endothelial surface as possible by means of a micromanipulator (WR-6; Narishige International, Tokyo, Japan). The NO electrode was connected to the amplifier (NO meter ISO-NO Mark 2; World Precision Instrument) and the signals were recorded. The NO concentration measured with the NO sensitive electrode reflects the NO released from the endothelium minus the NO clearanced by degradation and diffusion [19, 20].

Protocol
Left circumflex arterial rings with length of 1.5 cm were cut open along longitudinal axis and pinned down the organ chamber with the endothelium facing up. The organ chamber was filled with Krebs solution that was continuously perfused with 95% O2 to 5% CO2. After 60 to 120 minutes of equilibration in the organ chamber, the electrode was stabilized and the baseline of the current became stable. The NO measurement was then carried out. In group Ia (n = 6), NO release in arterial segments was stimulated with substance P (–8.5 log M). The artery was then washed by Krebs and incubated in hyperkalemic solution containing 20 mmol/L K+ for 1 hour at 37°C. In this high K+ (20 mmol/L) solution, Na+ was replaced by the equivalent K+ (14 mmol/L NaCl was replaced by 14 mmol/L KCl). The NO release was then repeated. In group Ib (n = 6), the protocol was the same as in group Ia, except that calcium ionophore A23187 (–6.5 log M) was used as NO stimulant. In our preliminary studies, NO-related relaxation was not changed after first endothelium-dependent relaxation by bradykinin and then washed out by Krebs solution. Our previous studies on NO release also showed that at least one repetition of bradykinin stimulation after 1 hour did not change the NO release.

Isometric Force Study
The coronary microarteries were cleaned of fat and connective tissue and cut into cylindrical rings of 2-mm length under a microscope. After the rings were mounted in a four-channel myograph (Model 610A; J.P. Trading, Aarhus, Denmark), a previously described method [17, 18, 21] was used to normalize vascular rings under a condition simulating the transmural pressure in vivo encountered by the coronary microartery. Briefly, the arterial 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
All rings were equilibrated for 30 minutes before and after normalization. To exclude the effect of hypoxia/ischemia, 95% O2 to 5% CO2 was aerated in the solution during the whole experimental period.

Effect of Nicorandil on Bradykinin-Induced, EDHF-Mediated Relaxation
Two rings taken from the same artery were allocated into two groups (group IIa, n = 8). One of them was immersed in Krebs solution and the other in Krebs containing 10 µmol/L nicorandil. After 1 hour incubation at 37°C, the ring was contracted with U46619 (–8 log M). When the contraction reached a plateau, EDHF-mediated relaxation was induced by bradykinin (–10 to –6.5 log M) with the presence of indomethacin (7 µmol/L), NG-nitro-L-arginine (L-NNA, 300 µmol/L), and oxyhemoglobin (HbO, 20 µmol/L). In our previous studies, the use of indomethacin, L-NNA, and HbO was demonstrated to be able to successfully rule out the role of prostacyclin (PGI2) and NO [17–19, 21].

Effect of Nicorandil on Bradykinin-Induced, EDHF-Mediated Relaxation After Hyperkalemic Exposure
Two rings taken from the same artery were allocated into two groups (group IIb, n = 16). One of them was immersed in hyperkalemic solution containing 20 mmol/L K+ for 1 hour at 37°C. In this high K+ (20 mmol/L) solution, Na+ was replaced by the equivalent K+ (14 mmol/L NaCl was replaced by 14 mmol/L KCl). The other ring was immersed in this hyperkalemic solution with addition of 10 µmol/L nicorandil for 1 hour at 37°C. The rings were then further contracted with U46619 (–8.4 log M). When the contraction reached a plateau, EDHF-mediated relaxation was induced by bradykinin (–10 to –6.5 log M) with the presence of indomethacin (7 µmol/L), L-NNA (300 µmol/L), and HbO (20 µmol/L) [17–19, 21].

Data Analysis
Nitric oxide was expressed as nM concentration. Relaxation was expressed as the percentage decrease in isometric force induced by U46619. The effective concentration of bradykinin that caused 50% of maximal relaxation was defined as EC50. The EC50 was determined from each concentration-relaxation curve by a logistic, curve-fitting equation: E = MAP/(AP + KP), where E is response, M is maximal relaxation, A is concentration, K is EC50 concentration, and P is the slope parameter. From this fitted equation, the mean EC50 ± SEM was calculated for each group.

Data were expressed as mean ± SEM and were analyzed with paired t test when the NO measurement was analyzed between the two groups and unpaired t test when the maximal relaxation was compared. Two-way analysis of variance (ANOVA) was used to compare the EDHF-mediated relaxation that was expressed as dose-response curves. Values of p less than 0.05 were considered significant.

Drugs
Drugs used and their sources were as follows: bradykinin, A23187, substance P, L-NNA, indomethacin, and Hb (Sigma, St. Louis, Missouri); U46619 (Cayman Chemical, Ann Arbor, Michigan); nicorandil was a generous gift by Chugai Pharmaceutical, Gotemba, Japan). The L-NNA (dissolved in distilled water) and indomethacin (dissolved in ethanol) were stored at 4°C. The solutions of U46619, HbO, and bradykinin were held frozen until required.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Effect of Hyperkalemia on the NO Release of Endothelium
Both substance P and A23187 elicited significant NO release from coronary endothelium.

Substance P at –8.5 log M (group Ia) elicited 66.2 ± 7.2 nmol/L of NO, which is significantly lower than that elicited by A23187 at –6.5 log M (group Ib: 82.4 ± 9.2 nmol/L, p < 0.01).

With exclusion of hypoxia/ischemia by continuous O2 supply, 1-hour normothermic exposure to 20 mmol/L K+ did not alter the NO release from coronary endothelium, either upon the stimulation of substance P (group Ia: 58.8 ± 5.0 nmol/L, p = 0.4, 95% confidence interval [CI]: –15.1 to 30.0 nmol/L) or of A23187 (group Ib: 86.6 ± 9.0 nmol/L, p = 0.5, 95% CI: –21.1 to 12.7 nmol/L; Figs 1 and 2).



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  		Fig 1. Substance P-induced nitric oxide (NO) release in porcine left circumflex coronary arteries before and after 1-hour exposure to 20 mmol/L K+ at 37°C (group Ia). Data are shown as mean ± SEM. No changes were observed in nitric oxide release with hyperkalemic exposure (n = 6, paired t test).

 


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  		Fig 2. Calcium ionophore A23187-induced nitric oxide release in porcine left circumflex coronary arteries before and after 1-hour exposure to 20 mmol/L K+ at 37°C (group Ib). Data are shown as mean ± SEM. No changes were observed in nitric oxide release with hyperkalemic exposure (n = 6, paired t test).

 
U46619-Induced Precontraction
The resting force of coronary microarteries was similar in each group. At the concentration of 10 µmol/L, nicorandil did not significantly alter the U46619-induced precontraction (11.9 ± 1.1 versus 14.6 ± 1.4 mN, p = 0.11, 95% CI: –0.8 to 6.1 mN), and this made the subsequent relaxation comparable. In group II, the precontraction was also comparable in the rings incubated in the hyperkalemic solution with or without nicorandil (p = 0.3).

Effect of Hyperkalemia on EDHF-Mediated Vasorelaxation
In comparison between the group IIa and IIb, the EDHF-mediated relaxation in coronary microarteries was markedly reduced after 1-hour exposure to hyperkalemia (84.2% ± 3.8% to 42.3% ± 6.0%, p < 0.001, 95% CI: 27.2% to 56.5%; compare Figs 3 and 4). Such EDHF-related endothelial dysfunction caused by hyperkalemia is consistent with our previous findings [6–9, 21].



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  		Fig 3. Concentration-relaxation curves for bradykinin in the coronary microarteries with the presence of indomethacin (7 µmol/L), NG-nitro-L-arginine (300 µmol/L), and oxyhemoglobin (20 µmol/L) (group IIa; n = 8 in each group). Data are shown as mean ± SEM (two-way analysis of variance). (Solid circles = control [Krebs]; open circles = pretreated with nicorandil, 10 µmol/L.)

 
Further data analysis showed that after hyperkalemic exposure, there was a tendency of right-shift in EC50 value of bradykinin (–7.91 ± 0.22 versus –8.64 ± 0.25 log M, p = 0.05, 95% CI: –1.47 to 0.01 log M).

Effect of Nicorandil on EDHF-Mediated Vasorelaxation With/Without Hyperkalemic Exposure
In the presence of nicorandil, bradykinin induced potent vasorelaxation with the maximum response mediated by EDHF of 82.0% ± 6.4%, similar to the control group (84.2% ± 3.8%, p = 0.6, two-way ANOVA; group IIa, Fig 3). In addition, the EC50 value of bradykinin was also maintained with the pretreatment of nicorandil (–8.63 ± 0.21 versus –8.64 ± 0.25 log M in control, p = 0.97, 95% CI: –0.72 to 0.69 log M). The EDHF-mediated maximal vasorelaxation that was reduced by hyperkalemia (group IIb, 42.3% ± 6.0%) was partially restored by addition of nicorandil in the solution containing 20 mmol/L K+ (group IIb, 50.7% ± 5.5%, p = 0.02, 95% CI: – 15.4% to –1.3%, t test; and p = 0.022, two-way ANOVA for the two curves; Fig 4), although there were no significant changes regarding EC50 (–8.12 ± 0.13 versus –7.91 ± 0.22 log M, p = 0.2, 95% CI: –0.15 to 0.56 log M).



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  		Fig 4. Concentration-relaxation curves for bradykinin in the coronary microarteries with the presence of indomethacin (7 µmol/L), NG-nitro-L-arginine (300 µmol/L), and oxyhemoglobin (20 µmol/L) after exposure to 20 mmol/L K+ with nicorandil (open circles) or without nicorandil (solid circles) at 37°C for 1 hour (group IIb). Data are shown as mean ± SEM. *p less than 0.05, compared with the control without nicorandil (n = 16, two-way analysis of variance).

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The present study demonstrated that potassium at the concentration of 20 mmol/L does not affect NO release in coronary arteries and that in coronary microcirculation, addition of nicorandil in cardioplegia may partially restore the EDHF-mediated endothelial function impaired by hyperkalemia

Effect of Hyperkalemia on NO Release in the Coronary Artery
This study for the first time provides direct evidence regarding the effect of hyperkalemia on NO release in the coronary artery. As is well-known now, NO is a major EDRF that plays the key role in the vascular regulation. Further, ischemia-reperfusion reduces endothelium-dependent relaxation [22], and this alteration is clearly due to the reduced release of NO in isolated working rat hearts [23]. However, little is known about the effect of hyperkalemia on the NO release without ischemia-reperfusion. Previous reports on the detrimental effect of hyperkalemic cardioplegia on endothelium or NO release were often combined the effect of hyperkalemia and that of ischemia-reperfusion injury [3–5, 24–26]. In addition, there are no reports on the effect of hyperkalemia on the NO release from the coronary endothelium by using direct electrochemical measurement. We therefore designed the present study to directly measure the NO release after hyperkalemic exposure, and we excluded the effect of ischemia-reperfusion by continuously bubbling the gas mixture of 95% O2 to 5% CO2 in the organ chamber. The NO release was directly measured with a membrane-type NO-sensitive electrode, a method demonstrated to be sensitive and specific in NO detection. We found that neither A23187 nor substance P-induced NO release in the porcine coronary artery was altered after 1 hour of normothermic exposure to 20 mmol/L K+. Our data suggested the tolerance of coronary endothelium to certain concentrations of potassium regarding NO release, and the data are consistent with our previous findings that the coronary endothelium-dependent relaxation as the whole is tolerant to potassium at the concentration of 20 mmol/L [27]. On the other hand, it remains unknown regarding the effect of higher concentrations of potassium on the NO release from the coronary endothelium.

Because the ability of the coronary endothelium to release NO is tolerant to the exposure to potassium at the concentrations usually used in cardioplegia (up to 20 mmol/L), the observed endothelial dysfunction after hyperkalemic exposure is obviously due to the impairment of another major EDRF, namely, EDHF, as demonstrated in previous studies [6–9, 21]. The susceptibility of EDHF to hyperkalemia was again confirmed in the coronary microarteries in the present study.

Effect of Nicorandil on EDHF-Mediated Function in the Coronary Microartery
As a KATP channel opener with a nitrate-like effect, the potent vasodilator nicorandil has been demonstrated effective in myocardial protection against ischemia-reperfusion [28]. Animal studies provided convincible evidence on the use of nicorandil in either crystalloid or blood cardioplegia, or histidine-tryptophan-ketoglurate solution to gain better cardioprotective effect [13, 14, 29]. Clinically, nicorandil has been successfully used. Hayashi and associates [16] have reported that nicorandil administration during cardiopulmonary bypass provides enhanced myocardial protective effects against ischemia-reperfusion in patients undergoing coronary artery bypass grafting. Orita and colleagues [30] have demonstrated that in 27 patients undergoing heart valve replacement surgery nicorandil (8 mg/L) and magnesium (20 mEq/L) solution given just before reperfusion as the terminal cardioplegia might reduce the postischemic reperfusion injury by the improvement of myocardial tissue blood flow and metabolism.

The effect of nicorandil on the coronary endothelial function was therefore evaluated in the present study. In the present study, hyperkalemic (20 mmol/L potassium) exposure did not affect NO release from the coronary endothelium. Taken together with previously reported results that potassium at this concentration impairs the EDHF-mediated vasorelaxation and hyperpolarization, we investigated the effect of nicorandil on EDHF-mediated relaxation in the coronary microartery.

Our data demonstrate that incubation with nicorandil did not alter the bradykinin-induced relaxation in the presence of PGI2 and NO inhibitors as well as the NO scavenger HbO, suggesting a preservative effect of nicorandil on EDHF function in the coronary microcirculation. Further, the present study shows that addition of nicorandil in hyperkalemic solution partially restored the EDHF-mediated relaxation that was impaired by hyperkalemia. Long and colleagues [15] reported that nicorandil added in hyperkalemic solution may attenuate the inhibitory effect of hyperkalemia on the release of EDHF. However, their study was performed in large epicardial coronary arteries and the so-called "EDHF" in the study is actually the combination of EDHF and residual NO that is resistant to L-NNA [17, 18]. It is now well known that to investigate the "true" EDHF function, use of a NO scavenger such as oxyhemoglobin in addition to NO synthase inhibitors is essential [17, 18]. In addition, nicorandil is a compound that releases NO [28]. The NO directly released from nicorandil may also contribute to the improved vasorelaxation.

Further, it is generally recognized that EDHF is more important in microcirculation than in large arteries [31]. In the present study, in the coronary microcirculation, we clearly demonstrated that addition of nicorandil to hyperkalemic solution partially protects the EDHF-related endothelial function against the impairment by hyperkalemia.

With regard to the mechanism of the protective effect of nicorandil, it is most likely related to the mechanism of EDHF-mediated smooth muscle relaxation. The EDHF relaxes vessels through opening potassium channels and hyperpolarizing the membrane that subsequently reduce calcium influx into the smooth muscle cell. Hyperkalemia exposure depolarizes the membrane potential, and therefore the action is opposite to that of EDHF [6, 8]. In contrast, the membrane hyperpolarization by the potassium channel opener nicorandil is synergistic to the effect of EDHF; and, therefore, it is anticipated that nicorandil may partially restore the reduction of EDHF function caused by hyperkalemia.

Clinical Implications
The present study demonstrates that the alteration of the coronary endothelial function by hyperkalemic (20 mmol/L potassium) cardioplegic solution is not related to NO release, but to the reduction of the EDHF-mediated relaxation. This alteration may be partially restored by addition of nicorandil in the hyperkalemic cardioplegic solution. Combined with the reported cardioprotective effect on cardiac myocytes [12–14, 16], our study supports the use of nicorandil in cardioplegic solution in cardiac surgery.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was fully supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project No. CUHK4127/01M and 4383/03M), China, and the Providence St. Vincent Medical Foundation, Portland, Oregon.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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