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Ann Thorac Surg 1998;66:1318-1322
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Potassium-channel opener in cardioplegia may restore coronary endothelial function

^a Division of Cardiothoracic Surgery, Department of Surgery, University of Hong Kong, Grantham Hospital, Aberdeen, Hong Kong

Accepted for publication May 8, 1998.

Address reprint requests to Prof He, Division of Cardiothoracic Surgery, University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Rd, Aberdeen, Hong Kong
e-mail: (gwhe{at}hkucc.hku.hk)

	Abstract

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Background. Depolarizing (hyperkalemic) solutions impair the coronary endothelial function through an endothelium-derived hyperpolarizing factor mechanism. I examined the hypothesis that potassium-channel openers may restore the impaired endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation when added to hyperkalemic cardioplegia.

Methods. The porcine coronary arteries were exposed to hyperkalemia (potassium, 20 or 50 mmol/L) or hyperkalemia plus the potassium-channel opener aprikalim at 0.1 mmol/L for 1 hour. Endothelium-derived hyperpolarizing factor-mediated relaxation (percentage of 30 nmol/L U46619 precontraction) was induced by calcium ionophore A23187 and bradykinin in the presence of indomethacin (7 µmol/L) and N-nitro-L-arginine (300 µmol/L).

Results. The endothelium-derived hyperpolarizing factor-mediated relaxation was significantly impaired by exposure to hyperkalemia (20 mmol/L: 24.9% ± 14.1% versus 88.0% ± 3.3% in control, p = 0.002 for A23187; 50 mmol/L: 40.5% ± 12.3% versus 76.5% ± 3.8%, p = 0.003 for bradykinin). This reduced relaxation was significantly recovered by addition of aprikalim into the hyperkalemic (20 mmol/L) solution in A23187 experiments (81.2% ± 4.8%, p = 0.002) but only slightly recovered when added into the higher concentration of potassium (50 mmol/L) in bradykinin experiments (56.1% ± 4.7%, p = 0.2).

Conclusions. Potassium-channel openers may preserve endothelium-derived hyperpolarizing factor-mediated coronary relaxation when added to traditional hyperkalemic cardioplegia. This effect is significant when the potassium concentration is 20 mmol/L but partially lost when it reaches 50 mmol/L. This study may provide new insights into cardioprotection during open heart operations.

	Introduction

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Use of depolarizing cardioplegia (potassium [K] at high concentrations, usually 10 to 20 mmol/L) is the most common method for myocardial preservation in open heart operations [1]. Despite the cardioprotective effect, depolarizing cardioplegia causes depolarization of the membrane potential by extracellular hyperkalemia resulting in energy storage depletion and calcium overload [2]. In contrast to the effect of depolarizing cardioplegia, the natural resting state of the cardiac myocyte is at hyperpolarized membrane potentials [2, 3]. Few channels or pumps are activated at hyperpolarized potentials, and there is little metabolic demand on the ventricular myocyte in this status.

In the view of the above concerns, hyperpolarizing cardioplegia has been proposed for cardiac arrest during open heart operations [2, 4]. Potassium-channel openers (KCOs) have been suggested to be the agent for hyperpolarizing cardioplegia [2, 4, 5]. One of the major K channels is the adenosine triphosphate-sensitive K channel. Adenosine triphosphate-sensitive KCOs inhibit the development of myocardial contracture, reduce the release of lactate dehydrogenase, and preserve intracellular adenosine triphosphate content during ischemia [6]. Therefore, use of adenosine triphosphate-sensitive KCOs as cardioplegia is a potential method for cardiac protection during open heart operations. Because of the hyperpolarizing effect of KCOs on the membrane potential of myocytes, cardioplegia using KCOs has been defined as "hyperpolarizing cardioplegia" [2]. Studies have demonstrated that hyperpolarizing cardioplegia significantly prolongs the period to the development of myocardial contracture [2, 4, 5] and affords a significantly better postischemic recovery of function than hyperkalemic depolarizing arrest [2].

During cardiac arrest, cardioplegia directly contacts the vascular endothelium. The effect of cardioplegia on endothelium is, therefore, another important aspect in myocardial protection [7–10]. In recent studies, my colleagues and I [11, 12] have demonstrated that hyperkalemic solutions affect coronary endothelial function by reducing endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The possible mechanism for this is through affecting K channels or direct depolarization of the membrane potential of the smooth muscle cell [13].

In contrast, the vasorelaxant action of KCOs may provide another important benefit to the myocardial protection. Potassium-channel openers are believed to relax blood vessels through hyperpolarization of the membrane potential of the smooth muscle. This subsequently affects voltage-operated calcium channels and intracellular calcium release, and therefore relaxes the vessel [6, 14]. The coronary vasodilatation obviously facilitates myocardial perfusion during the reperfusion period. Our recent study [15] has demonstrated that hyperpolarizing cardioplegia is superior to the depolarizing one in terms of protection of the coronary endothelial function.

In addition, a previous study demonstrated that when KCOs are added to hyperkalemic cardioplegia (St. Thomas cardioplegic solution), the cardioprotective effect of KCOs is still preserved [4]. However the mechanism of this effect has not been studied. I hypothesized that the cardioprotective effect of KCOs when added in hyperkalemic solutions may be related to its protective effect on the coronary endothelial function, particularly EDHF-related function. The present study was designed to examine this hypothesis.

	Material and methods

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Coronary arteries were obtained from porcine hearts that were harvested in a local abattoir. Immediately after the hog (either sex) was killed, the heart was rapidly removed, placed in a container filled with Krebs’ solution at 4°C, and transferred to the laboratory. Epicardial coronary arteries were dissected free from the surrounding connective tissue, cut into 3-mm-long rings, and mounted on a pair of stainless steel wires in organ chambers [16] filled by Krebs’ solution at 37°C. The Krebs’ solution had the following composition (in millimoles per liter): Na⁺, 144; K⁺, 5.9; Ca²⁺, 2.5; Mg²⁺, 1.2; Cl^-, 128.7; HCO₃^-, 25; SO₄^2-, 1.2; H₂PO₄^-, 1.2; and glucose, 11. The solution was aerated with a gas mixture of 95% O₂ and 5% CO₂ at 37°C. Six organ chamber arrangements were run concurrently.

A previously described organ-chamber technique [16] was used to normalize vascular rings under a pressure simulating the conditions encountered at the artery at its normal transmural pressure, according to their own length-tension curves. The normalization procedure was performed with a computerized program.

The endothelium was intentionally preserved by cautiously dissecting and mounting the rings [12]. To examine the endothelium-dependence of the relaxation (n = 4 to 7 in each group), in some rings, the endothelium was removed mechanically by using a fine wood stick moistened with Krebs’ solution to gently rub the intima of the rings. This method has been demonstrated to be able to eliminate the endothelium-dependent relaxation in the coronary artery [12, 16]. In endothelium-denuded rings, nitroglycerin (-4.5 log mol/L) was added at the end of the experiments to test whether those rings were still able to be relaxed with this endothelium-independent vasorelaxant agent [8, 12].

Protocol
All rings were equilibrated for 30 minutes before and after normalization. U46619 (30 nmol/L) was then added into the organ chamber to contract the rings. When the contraction reached a stable plateau (usually 10 minutes), cumulative concentration-response curves were established for A23187 or bradykinin. The concentrations were -10 to -6.5 log mol/L. To isolate EDHF-mediated relaxation from other endothelium-derived relaxing factors, the experiments were conducted in the presence of indomethacin (7 µmol/L), a cyclooxygenase inhibitor, and N^G-nitro-L-arginine (300 µmol/L), a nitric oxide biosynthesis/release inhibitor.

A23187-induced EDHF-mediated relaxation
In the control group, the concentration-relaxation curves were established without exposure to hyperkalemia. For the hyperkalemia group, in separate experiments, rings were exposed to hyperkalemic solutions containing 20 mmol/L K in the Krebs’ solution. After exposure for 1 hour, the chamber solutions were changed back to normal Krebs’ solution again and the rings were frequently washed with Krebs’ solution to restore the baseline. The concentration-relaxation curves to A23187 were established.

In the hyperkalemia and aprikalim group, the protocol was the same as in the hyperkalemia group except that in these experiments, the KCO aprikalim (0.1 mmol/L) was added into the bath solution in addition to the hyperkalemia.

Bradykinin-induced EDHF-mediated relaxation
The protocol was similar to the aforementioned. However, in the bradykinin experiments, the K concentration was 50 mmol/L instead of 20 mmol/L to test the effect of higher concentrations on the EDHF-mediated relaxation.

Indomethacin and N^G-nitro-L-arginine were added 30 minutes before the concentration-relaxation curves for A23187 or bradykinin were started. Only one concentration-relaxation curve (either for A23187 or bradykinin) was obtained from each coronary ring. From a number of rings in each group of experiments, a mean concentration-relaxation curve was constructed. During the experiments, the solutions in the organ chamber were continuously aerated with a mixture of 95% O₂ and 5% CO₂ to exclude the effect of ischemia.

Data analysis
The effective concentration of the relaxation agent that caused 50% of maximal contraction (or relaxation) was defined as EC₅₀. The EC₅₀ was determined from each concentration-relaxation curve by a logistic, curve-fitting equation: where E is response, M is maximal contraction (or relaxation), A is concentration, K is EC₅₀ concentration, and p is the slope parameter [16]. From these fitted equation, the mean EC₅₀ value ± standard error of the mean was calculated for each group.

Statistical analysis
Data were analyzed by analysis of variance (followed by Scheffé F test). Values of p less than 0.05 were considered significant.

Drugs
Drugs used and their sources were as follows: bradykinin, A23187, N^G-nitro-L-arginine, and indomethacin (Sigma, St. Louis, MO); U46619 (Cayman Chemical, Ann Arbor, MI). N^G-nitro-L-arginine (dissolved in distilled water) and indomethacin (dissolved in ethanol) were stored at 4°C. The solution of U46619 and bradykinin was held frozen until required.

	Results

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Comparison of precontraction
Precontraction by U46619 was little affected by incubation with hyperkalemia or its combination with aprikalim. The precontraction forces in the A23187 studies were 12.2 ± 0.9, 13.8 ± 2.5, and 12.1 ± 1.2 g, respectively, for the control, K 20 mmol/L, and K 20 mmol/L + aprikalim groups (n = 8 in each group; not significant). In the bradykinin studies the precontraction forces were 11.4 ± 1.1, 10.0 ± 0.4, and 13.1 ± 1.4 g, respectively, in the control, K 50 mmol/L, and K 50 mmol/L + aprikalim groups (not significant).

A23187-induced relaxation
The EDHF-mediated relaxation in this group was 88.1% ± 3.3% (n = 8). Exposure to hyperkalemia reduced this relaxation to 24.9% ± 14.1% (n = 8; p < 0.001). This reduced relaxation was recovered by addition of aprikalim into the hyperkalemic solution (81.2 ± 4.8%, n = 8; p = 0.2 compared with the control and p = 0.002 compared with the K 20 mmol/L treatment) (Fig 1).

View larger version (16K): [in this window] [in a new window]   Fig 1. Mean concentration (-log mmol/L)–relaxation (% of contraction by U46619 30 nmol/L) curves for calcium ionophore A23187. Symbols represent data averaged from a group of rings. Vertical bars are 1 standard error of the mean of the response at each concentration. All experiments were performed in the presence of indomethacin (7 µmol/L) and NG-nitro-L-arginine (300 µmol/L). (Black circles = control group [n = 8]; black triangles = K20 group, treated with potassium at a concentration of 20 mmol/L for 1 hour [n = 8]; white circles = K20 + APK group, treated with potassium [20 mmol/L] and aprikalim [100 µmol/L] for 1 hour [n = 8]; white triangles = E- group, endothelium-denuded [n = 4].) p < 0.001, compared with the control.

Bradykinin-induced relaxation
The EDHF-mediated relaxation in this group was 76.5% ± 3.8% (n = 13). Exposure to hyperkalemia (50 mmol/L) reduced this relaxation to 40.5% ± 12.3% (n = 7; p = 0.003). This reduced relaxation was partially recovered by addition of aprikalim into the hyperkalemic solution (56.1% ± 4.7%; n = 7), but the difference did not reach statistical significance (p = 0.2) (Fig 2).

View larger version (21K): [in this window] [in a new window]   Fig 2. Mean concentration (-log mol/L)–relaxation (% of contraction by U46619 30 nmol/L) curves for bradykinin. Symbols represent data averaged from a group of rings. Vertical bars are 1 standard error of the mean of the response at each concentration. All experiments were performed in the presence of indomethacin (7 µmol/L) and NG-nitro-L-arginine (300 µmol/L). (Black circles = control group [n = 8]; black triangles = K50 group, treated with potassium at a concentration of 50 mmol/L for 1 hour [n = 6]; white circles = K50 + APK group, treated with potassium [50 mmol/L] and aprikalim [100 µmol/L] for 1 hour [n = 8]; white triangles = E- group, endothelium-denuded [n = 4].) p < 0.01, compared with the control.

In endothelium-denuded rings, neither A23187 nor bradykinin induced any relaxation. This confirms that the relaxations observed in the present study were endothelium-dependent (see Figs 1, 2).

	Comment

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The present study has demonstrated that when added into hyperkalemic cardioplegia, KCOs may also preserve the EDHF-mediated coronary endothelial function, as it is used alone. However, this effect is dependent on K concentration. It is more significant at the K concentration of 20 mmol/L than at higher concentrations.

Endothelium-dependent relaxation is known to be due to a variety of different endothelium-derived relaxing factors. These are endothelium-derived nitric oxide prostacyclin, and EDHF. The nature of EDHF has not been finally identified, although most recently the cytochrome P450-monooxygenase metabolite of arachidonic acid has been suggested to be EDHF [17, 18]. Endothelium-derived hyperpolarizing factor induces vascular smooth muscle relaxation via hyperpolarization of the smooth muscle cells [19–23], which may involve K channels. In contrast, endothelium-derived nitric oxide mainly relaxes blood vessels through the cyclic guanosine monophosphate pathway. All of these endothelium-derived relaxing factors are released in response to the increase of intracellular (cytosolic free) calcium concentration in the endothelial cell [12].

Our previous studies [11–13] have demonstrated that when endothelium-derived nitric oxide and prostacyclin pathways are inhibited, there still is a significant endothelium-dependent relaxation that is obviously caused by the effect of the third component—EDHF. Further, we [15] have demonstrated that this EDHF-mediated coronary endothelial function is impaired by hyperkalemia exposure and preserved by KCOs as the hyperpolarizing cardioplegia. A question arising from here is what the effect would be when KCOs are added into a widely applied hyperkalemic cardioplegia such as St. Thomas’ cardioplegic solution. Because hyperpolarizing cardioplegia is still at the experimental stage, this question may have some clinical implications. Pignac and associates [4] have demonstrated that the combination of KCOs and St. Thomas’ cardioplegia provides better cardioprotective effect compared with St. Thomas’ cardioplegia alone. Although the mechanism is unclear, it may be related to the preservation of the coronary endothelial function, particularly the EDHF-mediated function. In fact, we [15] have demonstrated that aprikalim preserves this function but hyperkalemia reduces it. Therefore, a possible explanation for the better cardioprotective effect of the combination of KCOs and St. Thomas’ cardioplegia is that the reduced EDHF-mediated function by hyperkalemia is recovered by the addition of aprikalim.

The present study demonstrated that the protective effect of aprikalim on the EDHF-mediated relaxation when added into hyperkalemic cardioplegia may depend on the concentration of K. The recovery effect of aprikalim on the EDHF-mediated function was significant only when the K concentration was 20 mmol/L, although it did show some effect even when the K concentration was raised to 50 mmol/L (see Fig 2). This may be related to the degree of the depolarization of the smooth muscle membrane potential by hyperkalemia. Obviously, when the K concentration is higher, the higher degree of depolarization of the membrane potential may have a stronger inhibitory effect on the EDHF-mediated relaxation because this relaxation is related to hyperpolarization of the potential [12, 13].

The following question remains unanswered, however. Because K depolarizes the membrane potential of either the cardiac myocytes or the coronary smooth muscle cells but KCOs hyperpolarize them, what is the net effect on the membrane potential when these two agents are added together? The protective effect of the combination should be studied at the cellular level. This warrants further studies.

In conclusion, the present study demonstrates that when KCOs are used in combination with traditional hyperkalemic cardioplegia, it may preserve EDHF-mediated coronary relaxation that is reduced by hyperkalemia alone. This effect is significant when the K concentration is 20 mmol/L but partially lost when it reaches 50 mmol/L. This study may provide insights into cardioprotection during open heart operations.

	Acknowledgments

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This study was supported by Research Grant Council, Hong Kong (338/048/0004), Committee of Research and Conference Grants (337/048/0018 and 335/048/0079), and University Research Grants (344/048/0001 and 014.048.9602), University of Hong Kong. I sincerely thank Dr Cheng-Qin Yang at the Cardiovascular Research Laboratory, Grantham Hospital, Department of Surgery, University of Hong Kong, for her excellent experimental work.

The author is a member of the Institute for Cardiovascular Science and Medicine (ICSM), The University of Hong Kong.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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