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Ann Thorac Surg 2002;74:143-148
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Hypoxic preconditioning in coronary microarteries: role of EDHF and K+ channel openers

Zhen Ren, MDa, Qin Yang, MDb, H. Storm Floten, MDa, Guo-Wei He, MD, PhD*a,b

a Providence Heart Institute, Albert Starr Academic Center, Department of Surgery, Oregon Health and Science University, Portland, Oregon, USA
b Department of Surgery, The Chinese University of Hong Kong, Hong Kong, People’s Republic Of China

Accepted for publication April 2, 2002.

* Address reprint requests to Prof. He, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, NT, Hong Kong, People’s Republic Of China
e-mail: gwhe{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Hypoxic preconditioning may provide a useful method of myocardial protection in cardiac operations. The present study was designed to investigate the possible mechanisms of preconditioning regarding endothelium-derived hyperpolarizing factor (EDHF) and the effect of a potassium channel opener KRN4884 on the porcine coronary microartery in mimicking hypoxic preconditioning.

Methods. Porcine coronary microartery rings (diameter 200 to 500 µm) studied in a myograph were divided into seven groups: (1) control group; (2) hypoxia-reoxygenation group (hypoxia for 60 minutes followed by reoxygenation for 30 minutes); (3) preconditioning group (hypoxia for 5 minutes followed by reoxygenation for 10 minutes before hypoxia reoxygenation); (4) KRN4884 pretreatment group (KRN4884 was added into the myograph chamber 20 minutes before hypoxia reoxygenation); (5) 5-hydroxydecanoate + KRN group (5-hydroxydecanoate was given 20 minutes before KRN4884 pretreatetment); (6) glibenclamide (GBC) + KRN group (GBC was added 20 minutes before KRN4884 pretreatment); and (7) endothelium denuded group (the endothelium was removed). The endothelium-derived hyperpolarizing factor-mediated relaxation to bradykinin was studied in the rings precontracted with U46619 in the presence of N{omega}-nitro-L-arginine and indomethacin.

Results. The maximal relaxation induced by bradykinin was reduced in hypoxia reoxygenation (40.7% ± 2.8% vs 66.9% ± 2.5% in control, p = 0.000). This reduced relaxation was recovered in either preconditioning (64.6% ± 4.6%, p = 0.002), or KRN4884 pretreatment (67.1% ± 3.6%, p = 0.000). The 5-hydroxydecanoate, but not GBC pretreatment abolished the effect of KRN44884 pretreatment (67.1% ± 3.6% vs 42.9% ± 3%, p = 0.001).

Conclusions. Hypoxia reoxygenation reduces the relaxation mediated by endothelium-derived hyperpolarizing factor in the coronary microartery. This function can be restored by either hypoxic preconditioning or the KATP channel opener KRN4884, and therefore KATP channel openers may provide similar effect as preconditioning. The mechanism is mainly related to the mitochondrial ATP-sensitive K+ channels.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Ischemic preconditioning has long been recognized to protect the heart from ischemia and reperfusion injury [1]. Many studies have shown that the cardioprotection of ischemic preconditioning can be equally abolished by different types of ATP-sensitive potassium (KATP) channel blockers [2, 3], but not by calcium or sodium channel blockers [4]. Furthermore, the application of various KATP channel openers (KCOs) may mimic ischemic preconditioning, improve postischemic recovery of contractile function, enhance reflow, and reduce infarct size [5, 6]. These studies suggested that the opening of KATP channels may account for the mechanisms of ischemic preconditioning.

Hypoxia-reoxygenation injury involves cardiomyocytes as well as the coronary vessels. In the past, the cardiomyocyte injury has been studied extensively. However, only in recent years have studies been focused on hypoxia-reoxygenation injury of coronary vessels. Although most studies showed that the hypoxic relaxation of coronary arteries involves the opening of KATP channels [7], the direct inhibition of Ca2+ channel activity [8], the releasing of nitric oxide, and the activation of protein kinase C and adenosine [9], and so forth, there is less consensus regarding the involvement of the KATP channel in the preconditioning phenomenon observed in the coronary microvasculature.

Vascular endothelium plays a key role in regulating vascular tone through releasing vasoactive substances. Endothelium-dependent relaxation is known to be due to a variety of different endothelium-derived relaxing factors. These include endothelium-derived nitric oxide, prostacyclin (PGI2), and the endothelium-derived hyperpolarizing factor (EDHF) [10–12]. EDHF induces vascular smooth muscle relaxation through hyperpolarization of the smooth muscle cell, which may involve potassium (K+) channels [9]. It has been suggested that EDHF plays an even more important role in the regulation of the vascular tone and blood flow distribution in the microcirculation than in the large conductance arteries [13]. Because the coronary microvascular system plays a key role in regulating myocardial perfusion, the EDHF-mediated function in the coronary microvascular system is particularly important [3, 14]. Our laboratory has focused our vascular studies on the EDHF-mediated function in both large and small coronary arteries [12–20]. However, the mechanism of preconditioning in coronary microvasculature has not been investigated.

There are two major types of KATPs: sarcolemmal and mitochondrial KATPs [21]. The effect of preconditioning by KCOs on microvessels with regard to these two KATP channels has not been studied. Recent studies have shown that KRN4884, a novel KATP channel opener, has a specificity for the coronary artery, and its potency for opening KATPchannels exceeds that of other related compounds [22]. It is known that KCOs may have protective effects for cardiomyocytes in ischemic or hypoxic preconditioning, but it remains unknown whether KRN4884 can mimic the effects of hypoxic preconditioning on the coronary microartery.

Therefore, the present study was designed to investigate the possible mechanisms of preconditioning with regard to EDHF and the effects of KRN4884 on the porcine coronary microartery in mimicking hypoxic preconditioning.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Preparation and mounting of microarterial rings
Fresh porcine hearts collected from a local slaughterhouse were placed in a container filled with cold (4°C) Krebs solution and immediately transferred to the laboratory. Intramyocardial coronary arteries (the tertiary branches of the left anterior descending artery) in diameters of 190 to 490 µm (389.9 ± 7.1 µm) were carefully dissected out. The endothelium was intentionally preserved by cautiously dissecting and mounting the rings. In some rings, to examine the endothelial dependence of the relaxation, the endothelium was removed mechanically by using a human hair (approximately 60 µm in diameter) placed into the lumen to rub the luminal surface. The vessel was cleaned of the surrounding myocardium and cut into cylindrical rings of 2 mm long under a microscope. The rings were guided a suitable length through the lumen by a pair of a stainless steel wires (40 µm in diameter). One wire was fixed tightly on the jaw in a 2-channel myograph (Model 500A, JP Trading, Aarhus, Denmark) [13, 14], and the other wire was passed lightly through the vascular lumen and anchored onto another jaw. These two wires were attached to a force transducer or a micrometer, respectively. An adjustable micrometer can pull the jaws apart and stretch the artery between the 2 parallel wires. A calibrated force transducer was used to measure the force, with the output shown on a computer screen and printed on a printer. Two organ chamber arrangements in the same myograph were run concurrently.

The Krebs solution 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, and glucose 11. During the experiment, the solution at 37°C was aerated with a gas mixture of 95% O2 + 5% CO2 (normoxia, the partial pressure of oxygen [PO2] more than 200 mm Hg). Hypoxic condition was induced by switching bubbling gas from 95% O2 + 5% CO2 to 95% N2 + 5% CO2 (hypoxia, PO2 < 15 mm Hg). Partial pressure of oxygen was measured by an Oxygen Meter (Model 781, Strathkelvin Instrument, Glasgow, Scotland, UK).

Normalization
All rings were equilibrated for 45 minutes before and after normalization. In myograph (Model 500A), the normalization procedure was performed automatically. The artery rings were progressively stretched until the passive transmural pressure reached 100 mm Hg, and then the pressure was immediately released. The internal circumference was set at the circumference equivalent to 90% of that at a passive transmural pressure of 100 mm Hg [13, 14]. Only arterial rings in the internal diameter of 190 to 490 µm at the pressure of 100 mm Hg were used in the present study.

Protocol
The experimental protocols are depicted in Figure 1. Seven groups (n = 8 in each group) were studied:

  1. Control group, normoxia (PO2 >200 mm Hg).
  2. Hypoxia-reoxygenation group: 60-minute hypoxia (PO2 = 5.7 ± 0.8 mm Hg), followed by 30-minute reoxygenation.
  3. Preconditioning group: 5-minute hypoxia (PO2 = 13.2 ± 1.1 mm Hg), followed by 10-minute reoxygenation before the hypoxia-reoxygenation.
  4. KRN4884 pretreatment group: KRN4884 (30 µmol/L) was added into the myograph chamber 20 minutes before the hypoxia-reoxygenation.
  5. 5-hydroxydecanoate + KRN group: sodium 5-hydroxydecanoate ([5-HD], 10 µmo/L, a specific mitochondrial KATP blocker) was added into the chamber 20 minutes before the KRN4884 (30 µmol/L) pretreatment.
  6. 6. GBC + KRN group: GBC (a nonselective blocker of KATP channels, 3 µmol/L) was given into the chamber 20 minutes before the KRN (30 µmol/L) pretreatment.
  7. Endothelium-denuded group: endothelium was removed for dose-response curves to bradykinin (BK).



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  		Fig 1. Schematic diagram of the experiment protocols. (5-HD = 5-hydroxydecanoate; 5-HD + KRN group = pretreatment with sodium 5-hydroxydecanoate [10 µmol/L] before KRN4884 [30 µmol/L]; Control group = normoxia; E-group = endothelium was removed; GBC = glibenclamide; GBC + KRN group = pretreatment with GBC [3 µmol/L] before KRN4884 [30 µmol/L]; H-R group = hypoxia-reoxygenation group; KRN group = pretreatment with KRN4884 [30 µmol/L]; PC group = preconditioning group.)

 
After the procedure described above, the rings were washed with Krebs solution and equilibrated for another 30 minutes. The following relaxation curves were then established.

BK-induced EDHF-mediated relaxation
N{omega}-nitro-L-arginine ([L-NNA], 300 µmol/L), a nitric oxide synthase inhibitor, and indomethacin (7 µmol/L), a cycloxygenase inhibitor, were added into the chamber for 20 minutes except in the endothelium-denuded rings. U46619 was then added into the chamber to contract the rings. The concentration of U46619 varied from 3 to 100 nmol/L in different groups to reach a similar level of precontraction, because in arteries treated with KRN4884 due to the depression effect of KRN4884, higher concentrations of U46619 were needed to reach a similar contraction force with other groups. When the contraction reached a stable plateau, cumulative concentration-relaxation curves to BK (-10 to -6.5 log M) were established. Only one concentration-relaxation curve was obtained from each ring. From eight rings, a mean concentration-relaxation curve was constructed. The relaxation was expressed as a percentage of the contraction force induced by U46619.

Drugs
The following drugs were used: BK, L-NNA, indomethacin, and GBC (Sigma, St. Louis, MO); U46619 (Cayman Chemical, Ann Arbor, MI); sodium 5-hydroxydecanoate (Research Biochemical Inc, Natick, MA); KRN4884 (a generous gift by Pharmaceutiocal Research Laboratory of Kirin Brewery Co Ltd, Japan). KRN4884 was dissolved in dimethyl sulfoxide. L-NNA (dissolved in distilled water) and indomethacin (dissolved in ethanol) were stored at 4°C. The solution of U46619 was held frozen until required.

Data analysis
The effective concentration of the constrictor (or dilator) agent that caused 50% of maximal contraction (or relaxation) was defined as EC50. The EC50 was determined from each concentration-contraction (or relaxation) curve by a logistic, curve-fitting equation: E = MAP/(AP + KP), in which E is the response, M is the maximal contraction (or relaxation), A is the concentration, K is the EC50 concentration, and p is the slope measurement [11]. A computerized program was used for the curve fitting. From this fitted equation the mean EC50 value ± standard error of the mean was calculated in each group.

Statistical analyses
All statistical analyses were performed using SPSS 9.0 software (SPSS Inc, Chicago, IL). Data were expressed as mean ± standard error of the mean with 95% confidence intervals where appropriate. One-way analysis of variance (ANOVA) was used to test statistical significance among groups regarding the maximal response or EC50. Scheffe’s F test was used as a posthoc test between groups. A p value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Resting vessel parameters
The mean internal diameter of the rings at an equivalent transmural pressure of 100 mm Hg (D100) was 389.9 ± 7.1 µm (190 to 490 µm) as determined from the normalization procedure. When the coronary microartery rings were set at a resting diameter of 0.9 x D100, the equivalent transmural pressure was 62.3 ± 0.4 mm Hg, and the resting force was 4.5 ± 0.1 mN. There was no significant difference among the groups with regard to the diameter and resting force (all p > 0.05) (Table 1).


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  		Table 1. Diameter and Resting Force of Coronary Microarteriesa

 
Comparison of precontraction by U46619
There were no significant differences in the precontraction force by U46619 (-8.5 log M) among the groups (p = 0.3, ANOVA) (Fig 2A).



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  		Fig 2. (A) Precontraction force induced by U46619 (-8.5 to -7 log M) in the seven groups in porcine coronary microarteries. All values are mean ± standard error. In each group, n = 8; p = 0.92, analysis of variance among the seven groups (Scheffe’s F test). (B) Concentration-relaxation (percentage of precontraction by U46619 -8.5 log M) curves for bradykinin in porcine coronary microarteries. All values are mean ± standard error. In each group, n = 8. (5-HD + KRN group = pretreatment with sodium 5-hydroxydecanoate [10 µmol/L] before KRN4884 [30 µmol/L]; Control group = normoxia; E-group = endothelium denuded; GBC + KRN group = pretreatment with glibenclamide [3 µmol/L] before KRN4884 [30 µmol/L]; H-R group = hypoxia-reoxygenation group; KRN group = pretreatment with KRN4884 [30 µmol/L]; PC group = preconditioning group.) *p less than 0.05; **p less than 0.01, compared with H-R or 5-HD + KRN group (analysis of variance; Scheffe’s F test).

 
BK-induced relaxation mediated by EDHF
In the six groups of the endothelium-preserved rings with the presence of L-NNA (300 µmol/L) and indomethacin (7 µmol/L), BK induced remarkable relaxation mediated by EDHF in a concentration-dependent manner. However, among the six groups, there was a significant difference in the maximal relaxation induced by BK (p = 0.000, ANOVA). BK-induced relaxation at the concentration of 300 nmol/L was significantly less in the hypoxia-reoxygenation group (40.71% ± 2.8%) than in the control group (66.9% ± 2.5%; p = 0.000; 95% confidence interval [CI]: 9.1% to 43.4%; Scheffe’s F test). The reduced relaxation was recovered in the KRN4884 pretreatment group (67.0% ± 3.6%; p = 0.000; 95% CI: 9.2% to 43.5%) or in the preconditioning group (64.6% ± 4.6%; p = 0.002; 95% CI: 6.7% to 41.0%). The effect of KRN4884 was abolished by 5-HD (5-HD + KRN; 67.0% ± 3.6% vs 42.9% ± 3.0%; p = 0.001; 95% CI: 6.9% to 41.3%) but not by GBC (GBC + KRN; 67.0% ± 3.6% vs 61.2% ± 3.9%; p = 0.919) (Fig 2B).

In the endothelium-denuded rings, the BK-induced relaxation was abolished.

With regard to sensitivity, there was a significant difference in EC50 among the groups (p = 0.000; ANOVA). The EC50 value for BK was significantly higher in the hypoxia-reoxygenation group (-7.38 ± 0.12 log M) than in the control group (-8.05 ± 0.11 log M; p = 0.000; 95% CI: -1.01 to -0.26 log M; Scheffe’s F test) or in the preconditioning group (-7.89 ± 0.06 log M; p = 0.008; 95% CI: -0.09 to 0.91 log M), or in the GBC + KRN group(-7.81 ± 0.04 log M; p = 0.037; 95% CI: -0.02 to 0.84 log M).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In the present study, for the first time [1], we found that hypoxia reoxygenation impairs the L-NNA-resistant and indomethacin-resistant, endothelium-dependent relaxation (mediated by EDHF) in the coronary microartery [2]. In addition, we found that hypoxic preconditioning restores the EDHF-mediated endothelial function [3], and that the potassium channel opener KRN4884 mimics the protective effect of hypoxic preconditioning on this endothelial function, [4] and also that the protective effect of KCOs may be mainly related to the function of the mitochondrial KATP channel.

Role of EDHF-mediated relaxation in coronary microarteries
It is well known that that EDHF hyperpolarizes vascular smooth muscle cells by activating K+ channels, which leads to the closure of voltage-dependent Ca2+ channels, the reduction of intracellular free Ca2+, and subsequently the relaxation of blood vessels [11].

We have previously reported that EDHF plays a role in large conductance coronary arteries [11, 12, 15, 19, 20] as well as in microarteries [13, 14]. In the present study, because nitric oxide and cyclooxygenase pathways were blocked by L-NNA and indomethacin, the residual relaxation (66.9%) by BK is mainly mediated by the non-nitric oxide and noncyclooxygenase mechanism (ie, EDHF).

In the present study, we have noted that, after 60-minute hypoxia followed by 30-minute reoxygenation, the residual (resistant to L-NNA and indomethacin) relaxation was significantly reduced (40.7% ± 2.8%; p = 0.000), and this relaxation was completely recovered (64.6% ± 4.6%) in the hypoxic preconditioning group. These results show that the EDHF-mediated relaxation is impaired by the hypoxia-reoxygenation and is recovered by hypoxic preconditioning. On the basis of the previous studies suggesting that the mechanism of EDHF is related to K+ channels and hyperpolarization of the membrane potential [11, 13, 23], we hypothesized that the mechanism of the observed reduction of the EDHF-mediated relaxation is related to the inhibition of KATP channels due to hypoxia. The hypoxic preconditioning may open K+ channels and hyperpolarize the membrane [24], subsequently the voltage-operated Ca2+ channels are inhibited, and therefore the Ca2+ influx is reduced and causing vessel relaxation [25]. A recent study also showed that hypoxic preconditioning reduced the intracellular calcium concentration accumulation in coronary vascular smooth muscle and attenuated the vascular contraction [26].

The restoration of the EDHF function is most likely related to the protection of the function of KATP channels.

Mechanism of KRN4884 mimicking the effects of hypoxic preconditioning on coronary microarteries
KRN4884, as a novel KATP channel opener, has a specificity for the coronary artery and is potent for opening KATP channels [22]. KRN4884 directly stimulates the opening of KATP and causes hyperpolarization. This prevents Ca2+ entry through inhibiting the voltage-dependent Ca2+ channel, reduces intracellular free Ca2+, and decreases the Ca2+ sensitivity of contractile elements [22, 27]. Subsequently the vessel is relaxed. We have previously reported that KRN4884 has remarkable vascular relaxant effects on human conduit arteries used as coronary bypass grafts [18], and potassium channel opener in cardioplegia may restore coronary endothelial function [16, 19, 20]. In this study, we have found that KRN4884 pretreatment significantly depressed the maximal contraction induced by U46619 compared with the control group (Fig 2) and remarkably recovered the relaxation reduced by hypoxia-reoxygenation. These results demonstrate that the KRN4884 pretreatment can mimic the effects of hypoxic preconditioning in the protection of the EDHF-mediated endothelial function.

Studies suggested that there are two types of KATP channels: sarcolemmal and mitochondrial KATP channels [19]. Recently there has been growing evidence that the mitochondrial KATP channel is the receptor for cardioprotective actions of K+ channel openers [7]. As compared with GBC, 5-HD is an effective blocker of mitochondrial KATP channels [28] and has ischemia selectivity [29]. Therefore, 5-HD may be preferable to GBC as a KATP antagonist when determining the involvement of KATP channels in ischemic preconditioning. In the present study, we have found that 5-HD, but not GBC pretreatment, abolished the inhibitory effects of KRN4884 on the contraction by U46619 (Fig 2) and the maximal relaxation recovered by KRN4884. The present study shows that GBC, at the concentration we used, probably mainly blocks the sarcolemmal KATP and that KRN4884 mimics the effects of hypoxic preconditioning mainly through the mitochondrial KATP channels. This is in accordance with the study suggesting that the mitochondrial KATP channel appears to be an end effector of preconditioning against ischemia [30].

Limitation of the study
The present study was an in vitro vascular study. Although the study suggests that potassium channel openers may protect the EDHF-mediated relaxation through the mitochondrial KATP, the mechanism and its relationship with sarcolemmal-free calcium concentration are unclear. Furthermore, the role of preconditioning of coronary arteries, compared with that of the cardiac myocytes, in cardioprotection is unclear. Further studies are necessary to clarify these points.

In conclusion, the present study suggests that in coronary microvascular system hyoxia-reoxygenation reduces the EDHF-mediated endothelial function and this function can be restored by either hypoxic preconditioning or KCOs. The mechanism of the protective effect of KCOs is mainly related to the mitochondrial KATP. These findings strongly support the possibility of pharmacological agents duplicating the cardioprotective effects of hypoxic preconditioning in the coronary circulation by selective opening of mitochondrial KATP channels. Therefore, these findings have strong clinical implications with regard to myocardial protection during cardiac operations.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The work described in this article was fully supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project No. CUHK7246/99M and CUHK4127/01M), China, and the Providence St. Vincent Medical Foundation, Portland, Oregon. Dr Ren was a Starr-He International Postdoctoral Fellow, established by the Providence St. Vincent Medical Foundation, Portland, Oregon.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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J. Thorac. Cardiovasc. Surg., February 1, 2011; 141(2): 501 - 510.e1.
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Y.-Y. Dong, M. Wu, A. P.C. Yim, and G.-W. He
Effect of hypoxia-reoxygenation on endothelial function in porcine cardiac microveins.
Ann. Thorac. Surg., May 1, 2006; 81(5): 1708 - 1714.
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Y.-Y. Dong, M. Wu, A. P.C. Yim, and G.-W. He
Hypoxia-Reoxygenation, St. Thomas Cardioplegic Solution, and Nicorandil on Endothelium-derived Hyperpolarizing Factor in Coronary Microarteries
Ann. Thorac. Surg., November 1, 2005; 80(5): 1803 - 1811.
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M. D. Diodato, N. R. Shah, S. M. Prasad, S. L. Gaynor, J. S. Lawton, and R. J. Damiano Jr
Donor heart preservation with pinacidil: the role of the mitochondrial KATP channel
Ann. Thorac. Surg., August 1, 2004; 78(2): 620 - 627.
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G.-W. He, Z.-D. Ge, A. P. C. Yim, Q. Yang, and R.-Z. Zhang
Electrophysiologic and mechanical evidence of superiority of hyperpolarizing versus depolarizing cardioplegia in protection of endothelium-derived hyperpolarizing factor-mediated endothelial function: A study in coronary resistance arteries
J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1773 - 1780.
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