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Ann Thorac Surg 2001;71:642-647
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

ATP-sensitive potassium channel openers may mimic the effects of hypoxic preconditioning on the coronary artery

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

Accepted for publication June 28, 2000.

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, 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. This study was designed to investigate the effects of the potassium channel opener KRN4884 in mimicking hypoxic preconditioning on coronary arteries and to explore the possible mechanisms.

Methods. In the organ chamber, porcine coronary artery rings (n = 96) were studied in 6 groups (n = 16 in each group): I. Control: normoxia (pO₂ > 200 mmHg); II. Hypoxia-reoxygenation: 60-minute hypoxia (pO₂ < 15 mmHg) followed by 30-minute reoxygenation; III. Preconditioning: 5-minute hypoxia followed by 10-minute reoxygenation prior to hypoxia-reoxygenation; IV. KRN4884-pretreatment: KRN4884 (30 µM) was added into the chamber 20 minutes before hypoxia-reoxygenation; V. 5-HD-pretreatment: sodium 5-hydroxydecanoate (5-HD, 10 µM) was given 20 minutes prior to KRN4884-pretreatment; and VI. GBC-pretreatment: glibenclamide (GBC, 3 µM) was added 20 minutes prior to KRN4884-pretreatment. Concentration-contraction curves for U46619 (n = 8 in each group) were constructed. Concentration-relaxation curves for bradykinin (n = 8 in each group) related to endothelium-derived hyperpolarizing factor (EDHF) were established in the rings precontracted with U46619 (30 µM) in the presence of N-nitro-L-arginine (L-NNA, 300 µM) and indomethacin (7 µM).

Results. The maximal relaxation induced by bradykinin was reduced in hypoxia-reoxygenation (54.6 ± 4.3% versus 85.2 ± 5.7% in control, p = 0.001). This reduced relaxation was recovered in KRN4884-pretreatment (78.9 ± 3.7%, p = 0.014) or preconditioning (79.9 ± 3.7%, p = 0.009). 5-HD- but not GBC-pretreatment abolished the effect of KRN4884-pretreatment (78.9 ± 3.7% versus 53.5 ± 4.7%, p = 0.009).

Conclusions. Hypoxia-reoxygenation reduces the relaxation mediated by EDHF in the coronary artery. This function can be restored by either hypoxic preconditioning or the potassium channel opener KRN4884. The mechanism of such effect is mainly related to the mitochondrial ATP-sensitive K⁺ channels.

	Introduction

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Since Murry and colleagues [1] first described the phenomenon of ischemic preconditioning in dog heart in 1986, many investigators have demonstrated that this phenomenon occurs in all species tested, including humans. Most of the studies have shown that different types of ATP-sensitive potassium (K_ATP) channel blockers (such as glibenclamide or 5-hydroxydecanoate) can equally abolish the cardioprotection of ischemic preconditioning [2], whereas calcium or sodium channel blockers have no such effect [3]. Furthermore, the application of various K_ATP channel openers (KCOs) may mimic ischemic preconditioning and improve postischemic recovery of contractile function, enhance reflow, and reduce infarct size [2, 3]. These studies suggested that the mechanisms of ischemic preconditioning may be mainly related to the opening of K_ATP channels.

Hypoxia-reoxygenation injury involves myocytes as well as the coronary circulation. In the past, the myocyte injury has been extensively studied. However, only in recent years have studies been focused on hypoxia-reoxygenation injury of coronary circulation [4, 5]. Studies showed that hypoxic relaxation of coronary artery involves the opening of K_ATP channels [6], the direct inhibition of Ca²⁺ channel activity [7], the releasing of nitric oxide [8], and the activation of protein kinase C and adenosine [9]; on the other hand, the hypoxic contraction of coronary artery is due to the reduction of endothelium-derived nitric oxide [10].

Endothelium-dependent relaxation is known to be due to a variety of different endothelium-derived relaxing factors (EDRFs). These include endothelium-derived nitric oxide (NO), prostacyclin (PGI₂), and endothelium-derived hyperpolarizing factor (EDHF). EDHF induces vascular smooth muscle relaxation via hyperpolarization of the smooth muscle cell, which may involve potassium (K⁺) channels [11]. Recently, a study showed that the inhibition of NO synthesis does not affect the coronary artery dilation to hypoxia/ischemia, which suggests that EDRF (NO) does not mediate coronary response to hypoxia [12]. However, little has been known about the role of other EDRFs (such as EDHF) in ischemia-reoxygenation.

KRN4884, a novel K_ATP channel opener, has a specificity for the coronary artery [13] and its potency for opening K_ATP channels exceeds that of other related compounds [14]. As mentioned above, KCOs may have protective effects for myocytes in ischemic/hypoxic preconditioning, but it remains unknown whether KRN4884 mimics the effects of hypoxic preconditioning on the coronary artery. Further, there are two major types of K_ATPs—sarcolemmal and mitochondrial K_ATP [15, 16]. The effect of preconditioning by KCO on blood vessels with regard to these two K_ATP channels has not been studied.

In the present study, we investigated the effects of KRN4884 on the porcine coronary artery in comparison to hypoxic preconditioning with regard to the possible mechanisms concerning EDHF and the type of K_ATP channels involved.

	Material and methods

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Tissue preparation and organ chamber technique
Coronary arteries were obtained from porcine hearts that were harvested in a local abattoir. Immediately after the pig was killed, the heart was rapidly removed, placed in a container filled with Krebs solution at 4°C, and transferred to the laboratory. Epicardial left circumflex coronary arteries were dissected free of surrounding connective tissue, cut into 3-mm-long rings, and mounted on a pair of stainless steel wires in organ chambers filled with Krebs solution at 37°C. The endothelium was intentionally preserved by cautiously dissecting and mounting the rings. The Krebs solution had the following composition (in mM): 144 Na⁺, 5.9 K⁺, 2.5 Ca²⁺, 1.2 Mg²⁺, 128.7 Cl^-, 25 HCO₃^-, 1.2 SO₄^2-, 1.2 H₂PO₄^- and 11 glucose. The solution was aerated with a gas mixture of 95% O₂ + 5% CO₂ (normoxia, pO₂ > 200 mmHg) or 95% N₂ + 5% CO₂ (hypoxia, pO₂ < 15 mmHg. pO₂ was measured by an Oxygen Meter (model 781, Strathkelvin Instrument, Glasgow, Scotland) at 37°C. Four organ chambers were run concurrently.

A previously described organ-chamber technique [17] was used to normalize vascular rings under a pressure simulating the conditions encountered in the artery at its normal transmural pressure, according to their own length-tension curves. The normalization procedure was performed with a computerized program (VESTAND by Y-H He, Princeton University, Princeton, NJ).

Protocol
All the rings were equilibrated for 45 minutes before and after normalization.

Ninety-six rings were allocated in 6 groups as in the following:

1. Control group (n = 16): normoxia (pO₂ > 200 mmHg).
   
2. Hypoxia-reoxygenation group (n = 16): 60-minute hypoxia (pO₂ = 5.7 ± 0.8 mmHg), followed by 30-minute reoxygenation.
   
3. Preconditioning group (n = 16): 5-minute hypoxia (pO₂ = 13.2 ± 1.1 mmHg), followed by 10-minute reoxygenation prior to the hypoxia-reoxygenation.
   
4. KRN4884-pretreatment group (n = 16): KRN4884 (30 µM) was added into the organ chamber 20 minutes prior to the hypoxia-reoxygenation.
   
5. 5-HD-pretreatment group (n = 16): sodium 5-hydroxydecanoate (5-HD, 10 µM) was added into the organ chamber 20 minutes prior to the KRN4884-pretreatment.
   
6. GBC-pretreatment group (n = 16): glibenclamide (3 µM) was given into the organ chamber 20 min prior to the KRN-pretreatment.
   

After the above procedure, the rings were further divided into contraction group (n = 8 in each group) and relaxation group (n = 8 in each group).

U46619-induced contraction
In each contraction group (n = 8), 100 mM KCl was added into the organ chamber and the contraction force was recorded (rings were discarded if their contraction force to 100 K⁺ was less than 1 g). This contract force (to 100 mM KCl) was used as 100% to normalize the contraction induced by U46619. The ring was frequently washed to restore the baseline. Cumulative concentration-contraction curves were established for U46619 (-10 to -6.5 log M), a stable thromboxane A₂ mimetic. Only one concentration-contraction curve was obtained from each coronary ring. From eight rings, a mean concentration-contraction curve was constructed. The contraction was expressed as percentage of the contraction force induced by 100 mM K⁺.

Relaxation
Bradykinin-induced EDHF-mediated relaxation
In each relaxation group (n = 8), N-nitro-L-arginine (L-NNA, 300 µM), a nitric oxide synthase inhibitor, and indomethacin (7 µM), a cycloxygenase inhibitor, were added into the chamber for 20 minutes. U46619 (30 nM) was then added into the organ chamber to contract the rings, except in the group of the rings that were pretreated with GBC. In this group, the concentration of U6619 was 300 nM because the contraction by U46619 is generally depressed by the pretreatment by GBC. When their contraction reached a stable plateau (usually 10 minutes), cumulative concentration-relaxation curves to bradykinin (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 percentage of the contraction force induced by U46619 (30 nM, but 300 nM for GBC-pretreatment group).

Role of endothelium in KRN4884-induced relaxation
To examine the role of endothelium in the KRN4884-induced relaxation, the endothelium in six rings was removed mechanically by using a fine wood stick moistened with Krebs solution to gently rub the intima of the rings [11]. This method has been demonstrated to be able to eliminate the endothelium-dependent relaxation in the porcine coronary artery [11].

Drugs
The following drugs were used: BK, L-NNA, indomethacin, and glibenclamide (Sigma, St. Louis, MO); U46619 (Cayman Chemical, Ann Arbor, MI); 5-hydroxydecanoate (Research Biochemical Inc, Natick, MA); and KRN4884, which was a generous gift from the Pharmaceutical Research Laboratory of Kirin Brewery Co Ltd, (Gunma, Japan). KRN4884 was dissolved in dimethyl sulfoxide (DMSO). 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. Control experiments showed that neither DMSO nor ethanol affect the experimental results.

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 = MA^p/(A^p + K^p), where E is response, M is maximal contraction (or relaxation), A is concentration, and K is EC₅₀ concentration, and P is the slope parameter [17]. A computerized program was used for the curve-fitting. From this fitted equation, the mean EC₅₀ value ± SE of the mean was calculated in each group.

Statistical analysis
All statistical analysis was performed with SPSS9.0 software (SPSS Inc, Chicago, IL). Data were expressed as mean ± SE 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 post-hoc test between groups. p < 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 96 rings at an equivalent transmural pressure of 100 mmHg (D100) was 3.6 ± 0.1 mm, as determined from the normalization procedure. When the coronary artery rings were set at a resting diameter of 0.9 x D100, the equivalent transmural pressure was 69.7 ± 0.6 mmHg, and the resting force was 5.5 ± 0.2 g.

Contraction studies
K⁺ (100 mM)-induced contraction force
There was significant difference in the K⁺ (100 mM)-induced contraction among the 6 groups (p = 0.011, ANOVA). Comparing with 8.4 ± 1.3 g in hypoxia-reoxygenation group, the contraction by K⁺100 mM was 3.6 ± 1.0 g in GBC-pretreatment group (p = 0.042, 95% confidence interval for the difference of the mean [95% CI]: 0.1 9.6 g, Scheff’s F-test) (Fig 1A).

View larger version (20K): [in this window] [in a new window]   Fig 1. (A) Contraction force induced by K+ 100 mM in the 6 groups in porcine coronary arteries. Value are mean ± SE of the mean. p = 0.011, ANOVA among the 6 groups. *p < 0.05, compared with the force in the hypoxia-reoxygenation group (Scheffe’s F-test). (B) Concentration-contraction (% of 100 mM K+- induced contraction) curves to U46619 in porcine coronary arteries. Values are mean ± SE of the mean. p < 0.001 ANOVA among the 6 groups. *p < 0.05, compared with the maximal contraction in the control and other groups (Scheffe’s F-test). (H-R = hypoxia-reoxgenation; PC = preconditioning; 5-HD = 5-hydroxydecanoate; GBC = glybenclamide; KRN = KRN 4884.)

With regard to sensitivity, there was a significant difference regarding EC₅₀ among the 6 groups (P < 0.001, ANOVA). The EC₅₀ value for U46619 was remarkably increased in KRN4884-pretreatment (-7.24 ± 0.08 log M) than that in control (-8.07 ± 0.04 log M, p < 0.001, 95% CI: -1.2 -0.40 log M), or hypoxia-reoxygenation (-8.07 ± 0.06 log M, p < 0.001, 95% CI: -1.2 -0.41 log M), or preconditioning (-8.05 ± 0.07 log M, p < 0.001, 95% CI: -1.23 -0.38 log M), or 5-HD-pretreatment (-7.7 ± 0.1 log M, p = 0.028, 95% CI: -0.03 0.88 log M).

Relaxation studies
Role of endothelium in KRN4884-induced relaxation
There were no differences found in the relaxation to KRN4884 between the endothelium-intact and the endothelium-denuded rings (data not shown). This demonstrates that the KRN4884-induced relaxation is endothelium-independent.

Comparison of precontraction by U46619
There was a significant difference in precontraction by U46619 (-7.5 log M) among the groups (p = 0.001, ANOVA). Compared with 11.5 ± 2.2 g in hypoxia-reoxygenation group, the precontraction induced by U46619 was 4.8 ± 0.7 g in KRN4884-pretreatment (p = 0.007, 95% CI: 1.3 12 g, Scheffe’s F-test) or 5.5 ± 0.6 g in 5-HD-pretreatment (P = 0.02, 95% CI: 0.58 11.3 g). In GBC-pretreatment, the precontraction was 0 g to U46619 (-7.5 log M) and 8.8 ± 1.1 g to U46619 (-6.5 log M), respectively (Fig 2A). However, all the precontraction force in groups had no significant difference compared with the control (p > 0.05, ANOVA).

View larger version (23K): [in this window] [in a new window]   Fig 2. (A) Precontraction force induced by U46619 (-7.5 log M) in the 6 groups in porcine coronary arteries. Values are mean ± SE of the mean. p = 0.01, ANOVA among the 6 groups. *p < 0.05, **p < 0.01, compared with the precontraction force in the hypoxia-reoxygenation group (Scheffe’s F-test). Because the contraction to U46619 after pretreatment with GBC is low, -6.5 log M was used in this group (GBC#) to reach comparable precontraction force to U46619. (B) Concentration-relaxation (% of precontraction by 30 nM U46619, 300 nM in GBC-pretreatment group) curves for bradykinin in porcine coronary arteries. Values are mean ± SE of the mean. p < 0.001, ANOVA among the 6 groups. *p < 0.05, **p < 0.01, compared with the maximal relaxation in the hypoxia-reoxygenation or the 5-HD-pretreatment group (Scheffe’s F-test). (H-R = hypoxia-reoxgenation; PC = preconditioning.) 5-HD, GBC, and KRN: see the legend in Figure 1.

With regard to sensitivity, there was a remarkable difference in EC₅₀ among the 6 groups (p < 0.001, ANOVA). The EC₅₀ value for BK was significantly higher in hypoxia-reoxygenation (-7.79 ± 0.13 log M) than that in control (-8.69 ± 0.08 log M, p = 0.001, 95% CI: -1.53 -0.27 log M, Scheffe’s F-test) or in GBC-pretreatment (-8.47 ± 0.1 log M, p = 0.024, 95% CI: -1.3 -0.06 log M).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The present study has demonstrated, for the first time, 1) that hypoxia-reoxygenation impairs the L-NNA- and indomethacin-resistant endothelium-dependent relaxation (mediated by EDHF) in the coronary artery; 2) that hypoxic preconditioning restores the EDHF-mediated relaxation; 3) that the KCO KRN4884 may mimic the protective effect of hypoxic preconditioning on the EDHF-mediated relaxation; and 4) that the protective effect of KCOs may be related to the mitochondrial K_ATP channel rather than the sarcolemmal K_ATP channel.

Effects of hypoxia-reoxygenation and hypoxic preconditioning on EDHF-mediated relaxation
In this study, bradykinin was used to test the endothelium-dependent relaxation. Bradykinin, through a receptor mechanism, increases the intracellar Ca²⁺ concentration and stimulates the release of EDRFs (NO, PGI₂, and EDHF) in the endothelial cell [18]. Because the other two main components (NO and cyclooxygenase pathways) were blocked by L-NNA and indomethacin, the residual relaxation is through the non-NO and non-cyclooxygenase mechanism (ie, related to EDHF). In the present study, in the control (normoxia) rings pretreated with L-NNA and indomethacin, the relaxation by bradykinin was nearly full (85.2%) suggesting that, in the presence of L-NNA and indomethacin, EDHF plays an essential role in endothelium-dependent relaxation in the porcine coronary artery. This is in accordance with the results from our previous reports [11], as well as from others [19].

After 60-minute hypoxia followed by 30-minute reoxygenation, the residual (L-NNA- and indomethacin-resistant) relaxation was significantly reduced (54.6 ± 4.3%, p = 0.001). However, in the hypoxic preconditioning group, the reduced relaxation was almost completely recovered (79.9 ± 3.7%, p = 0.009). These results showed that the EDHF-mediated relaxation is impaired by the hypoxia-reoxygenation and is recovered by hypoxic preconditioning. When EDHF-mediated relaxation is reduced, the coronary artery may have a higher tendency to contract, and this may lead to coronary spasm. However, the hypoxic preconditioning may open K⁺ channels and hyperpolarize the membrane [20, 21]. Subsequently, the voltage-operated Ca²⁺ channels are inhibited and therefore the Ca²⁺ influx is reduced. This causes the vessel relaxation [22].

In the present study, the pretreatment in the different groups was related to the subsequent precontraction induced by U46619 (Fig 2A). Hypoxia-reoxygenation induced higher precontraction by U46619, whereas KRN4884-pretreatment led to remarkably lower precontraction, which is due to the effect of KRN4884 on the opening of K_ATP channels [13, 14]. More significantly, GBC-pretreatment also significantly inhibited the precontraction (0 g) induced by U46619 (-7.5 log M) and therefore higher concentration of U46619 (-6.5 log M) was required to reach the precontraction force (8.8 ± 1.1 g). As being suggested, sulphonylureas (such as glibenclamide) may interfere with the signal transduction process of prostanoid receptors, possibly at the level of the G-protein [23]. Our results that glibenclamide antagonized the response to U46619 are in accordance with others [23, 24].

Possible mechanism of KRN4884 mimicking the effects of hypoxic preconditioning on coronary arteries
As a novel K_ATP channel opener, KRN4884 has a specificity for the coronary artery [13] and is potent for opening K_ATP channels [14]. KRN4884 directly stimulates the opening of K_ATP in the smooth muscle 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 [13, 22]. Subsequently, the vessel is relaxed. In this study, we have found that KRN4884-pretreatment significantly depressed the maximal contraction induced by U46619 compared with other groups (Fig 1B) and remarkably recovered the relaxation reduced by hypoxia-reoxygenation (54.6 ± 4.3% versus 78.9 ± 3.7%, p = 0.014, Fig 2B). Since both K⁺ channel opener and EDHF relax the vascular smooth muscle through opening of K⁺ channels, these results may suggest that the mechanism of hypoxic preconditioning in the protection of the EDHF-mediated endothelial function may be related to K⁺ channels. However, this needs to be further studied.

It is suggested that there are two types of K_ATP channels, sarcolemmal and mitochondrial K_ATP channels [15, 16]. Recently, there is growing evidence that the mitochondrial K_ATP channel is the receptor for cardioprotective actions of K⁺ channel openers [25]. As compared to glibenclamide, 5-HD is an effective blocker of mitochondrial K_ATP channels [25, 26] and has ischemia-selectivity [27]. 5-HD may be preferable to glibenclamide as a K_ATP antagonist when determining the involvement of K_ATP channels in ischemic preconditioning [28]. In the present study, we have found that 5-HD-pretreatment, but not GBC, abolished the maximal relaxation recovered by KRN4884 (78.9 ± 3.7% versus 53.5 ± 4.7%, p = 0.009). These results further suggest that the mechanism of the effect of hypoxic preconditioning may be related to the mitochondrial K_ATP channels.

KCOs have other important clinical applications. Pharmacological K_ATP openers have been showed by numerous investigators to improve myocardial preservation for heart transplantation [29], and to be used as a hyperpolarizing cardioplegia [30]. These potential clinical applications of KCOs may enhance the importance of the findings from the present study.

We realize that the present study has its limitations. In the in vitro studies perfused with physiological solutions, the results may not be directly applied to physiological status where the organs are perfused with blood. Nevertheless, our study provides new insights into the mechanism of hypoxic preconditioning and the use of K⁺ channel openers in cardiac surgery.

In conclusion, the present study suggests that hypoxia-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 K_ATP rather than sarcolemmal K_ATP. These findings may have clinical implications with regard to myocardial protection during cardiac surgery, but further studies are needed in intact animals.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported by St. Vincent Medical Foundation, Portland, OR, and Hong Kong Research Grants Council grants (CUHK7280/97M and CUHK7246/99M). Doctor Ren is a Starr-He International Postdoctoral Fellows.

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