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Ann Thorac Surg 1996;61:1394-1399
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Hyperkalemia Alters Endothelium-Dependent Relaxation Through Non–Nitric Oxide and Noncyclooxygenase Pathway: A Mechanism for Coronary Dysfunction due to Cardioplegia

Cardiovascular Research Laboratory, Department of Surgery, University of Hong Kong, Grantham Hospital, Aberdeen, Hong Kong

Accepted for publication January 22, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Reported results of hyperkalemia (cardioplegia or organ preservation solutions) on endothelial function are contradictory. The endothelium-dependent relaxation is related to three major mechanisms: cyclooxygenase, nitric oxide, and endothelium-derived hyperpolarizing factor (K⁺ channel related). The present study was designed to test the hypothesis that hyperkalemia may alter endothelial function through non–nitric oxide and noncyclooxygenase pathways.

Methods. Porcine coronary artery rings (5 to 10 in each group) were studied in organ chambers under physiologic pressure. After incubation with 20 or 50 mmol/L K⁺ for 1 hour, the response to substance P, an endothelium-dependent vasorelaxant peptide, in K⁺ (25 mmol/L)-induced contraction was studied in the presence of the cyclooxygenase inhibitor indomethacin (7 µmol/L), the nitric oxide biosynthesis inhibitor N^G-nitro-L-arginine (L-NNA) (300 µmol/L), or the adenosine triphosphate–sensitive K⁺-channel blocker glybenclamide (3 µmol/L) in comparison with control arteries (69.8 ± 4.6% of K⁺ contraction).

Results. Without exposure to hyperkalemia, indomethacin (with or without glybenclamide) did not alter but L-NNA significantly reduced the relaxation (39.7% ± 3.7%, p < 0.001). After exposure to K⁺, the indomethacin- and L-NNA–resistant relaxation was further reduced (7.4% ± 3.2% for 20 mmol/L K⁺, p < 0.0001; or 13.5% ± 8.4% for 50 mmol/L K⁺, p < 0.05, compared with rings without exposure), whereas the indomethacin- and glybenclamide-resistant relaxation was not altered. Incubation with hyperkalemia (50 mmol/L) also significantly reduced the sensitivity (increased EC₅₀) of the indomethacin- and L-NNA–resistant relaxation (-9.75 ± 0.06 versus -9.33 ± 0.04 log M, p < 0.01).

Conclusions. Exposure to hyperkalemia reduces the indomethacin- and L-NNA-resistant, endothelium-dependent (endothelium-derived hyperpolarizing factor-related) relaxation. Our study may suggest a new mechanism of coronary dysfunction after exposure to hyperkalemia and open a new area for protection of coronary endothelium in cardiac surgery and for organ preservation in transplantation surgery.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Hyperkalemic solutions are widely used for cardioplegia and organ preservation. The potassium concentration usually ranges between 10 and 20 mmol/L in cardioplegic solutions and as high as 140 mmol/L in the University of Wisconsin solution to preserve organs for transplantation. During arrest of the heart or preservation period of the donor organ, the hyperkalemic solution contacts vascular endothelium directly. Therefore, it is important to know the effect of hyperkalemia on endothelium. An important question is whether exposure to hyperkalemic solutions alters endothelial function. In fact, this has been the focus of several recent studies [1–5]. However, a uniform conclusion regarding such effect has not been reached.

In perfused rat hearts, previous studies have suggested that infusion of hyperkalemic cardioplegic solution damages coronary endothelium [1]. In contrast, other researchers [2] and ourselves [3, 4] have demonstrated tolerance of endothelium to hyperkalemia. We have shown that exposure to hyperkalemic solutions for up to 4 hours does not alter the noncyclooxygenase pathway-mediated endothelium-dependent relaxation in porcine coronary arteries [3] or neonatal rabbit aortas [4].

Endothelium-dependent relaxation is known to be the effect of a variety of different endothelium-derived relaxing factors. These are endothelium-derived nitric oxide (EDNO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although the nature of EDHF has not been conclusively identified, most recently the cytochrome P450-monooxygenase metabolite of arachidonic acid has been suggested to be EDHF [6]. Endothelium-derived hyperpolarizing factor induces vascular smooth muscle relaxation through hyperpolarization of the smooth muscle cells [7–12], which may involve potassium (K⁺) channels [10–12]. In contrast, EDNO relaxes blood vessels through the cyclic guanosine monophosphate pathway and does not significantly hyperpolarize the vascular smooth muscle cells [6, 13]. However, all of these EDRFs are released in response to the increase of intracellular (cytosolic free) calcium concentration in the endothelial cell [6].

The effect of hyperkalemia on noncyclooxygenase and non–EDNO-mediated, endothelium-dependent (presumably EDHF-mediated) relaxation is unknown. We have hypothesized that the discrepancy between the observed results from beating heart experiments [1] and those from isolated blood vessels may be related to the effect of hyperkalemia on EDHF-mediated relaxation. If hyperkalemia alters this relaxation, it would have strong clinical implications because of the wide use of hyperkalemic solutions in cardiac surgery and organ transplantation.

The present study was designed to examine the effect of hyperkalemia without ischemia on indomethacin and N^G-nitro-L-arginine (L-NNA)-resistant (noncyclooxygenase and non-EDNO mediated), that is, EDHF-mediated endothelium-dependent relaxation in the porcine coronary artery.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
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 [14] filled by Krebs solution at 37°C. 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; SO₄^2-, 1.2; H₂PO₄^-, 1.2; and glucose, 11. The solution was aerated with a gas mixture of 95% O₂–5% CO₂ at 37°C. Four organ bath arrangements were run concurrently.

A previously described organ bath technique [14] was used to normalize vascular rings under physiologic pressure, according to their own length–tension curves. The normalization procedure was performed with a computerized program (VESTAND 2.1 by Yang-Hui He, Princeton University; Princeton, NJ).

The endothelium was intentionally preserved by cautiously dissecting and mounting the rings [15, 16]. In some rings, the endothelium was removed mechanically to examine the endothelium-dependence of the relaxation to substance P (SP). In endothelium-denuded rings, nitroglycerin (-4.5 log M) was added at the end of SP experiments to test whether those rings were still able to be relaxed with this endothelium-independent vasorelaxant [3].

Protocol
All rings were equilibrated for 30 minutes before and after normalization. Complying with the following protocols, K⁺ (25 mmol/L) was added into the organ chamber to contract the rings. This concentration of K⁺ is equal to the EC₅₀ of K⁺ in the porcine coronary artery, determined from the concentration–contraction curve to K⁺ in previous studies [3]. When the contraction reached a stable plateau (usually 10 minutes), cumulative concentration–response curves to SP were established. The concentrations were -12 to -8.5 log M for SP.

CONTROL.
The concentration–relaxation curves were established with the presence of various combinations of inhibitors: (1) indomethacin (7 µmol/L), a cyclooxygenase inhibitor; (2) indomethacin (7 µmol/L) and L-NNA (300 µmol/L), a nitric oxide biosynthesis/release inhibitor; and (3) indomethacin (7 µmol/L) and an adenosine triphosphate-sensitive K⁺ channel blocker, glybenclamide (GBM, 3 µmol/L).

HYPERKALEMIA TREATMENT.
In separate experiments, after equilibration rings were exposed to hyperkalemic solutions containing either 20 or 50 mmol/L K⁺ in Krebs solution. After exposure for 1 hour, the chamber solutions were returned to normal Krebs and the rings were frequently washed by Krebs for 30 minutes to restore baseline. Protocols (2) and (3) for the control group were repeated before the concentration–relaxation curves to SP were established.

Indomethacin, L-NNA, and GBM were added 30 minutes before the concentration–relaxation curves for SP were started. Only one concentration–relaxation curve 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 organ chambers were aerated continuously with a mixture of 95% O₂–5% CO₂.

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: E = MA^P/(A^P + K^P) where E is response, M is maximal contraction (or relaxation), A is concentration, K is EC₅₀ concentration, and p is the slope parameter [14]. From these fitted equations, 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's test) or unpaired t test. A p value less than 0.05 was considered significant.

Drugs
Drugs used and their sources were substance P, L-NNA, indomethacin, and GBM (Sigma, St. Louis, MO); L-NNA (dissolved in distilled water) and indomethacin (dissolved in ethanol) were stored at 4°C. Stock solutions of SP were held frozen until required. Glybenclamide was dissolved in 95% ethanol to 1 mmol/L.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Basal Tone and Comparison of Precontraction
The change of the basal tone by various inhibitors was minimal. In any group, indomethacin or indomethacin plus GBM did not affect the tone. However, indomethacin plus L-NNA slightly increased the tone. In the control rings, the change of the tone was 0.2 ± 0.1 g. In the rings treated with 20 mmol/L K⁺, the change of the tone was 0.2 ± 0.1 g. In the rings treated with 50 mmol/L K⁺, the change of the tone was 0.8 ± 0.1 g.

Precontraction by K⁺ was not affected by treatment with indomethacin and L-NNA (10.1 ± 1.6 versus 10.2 ± 0.5 g in the rings treated by 20 mmol/L K⁺ and 9.7 ± 0.9 g in the rings treated by 50 mmol/L K⁺, p > 0.05). However, the precontraction was decreased by the pretreatment with indomethacin and GBM (10.8 ± 1.6 versus 4.8 ± 1.3 g in the rings treated by 50 mmol/L K⁺, p < 0.05).

Substance P-induced Relaxation
In control rings, SP induced 69.8% ± 4.6% relaxation. Treatment with indomethacin (n = 6) or indomethacin plus GBM (n = 6) did not change the maximal relaxation (84.6% ± 3.8% with indomethacin and 73.3% ± 2.6% with indomethacin plus GBM, p > 0.05 by analysis of variance). However, the combination of indomethacin and L-NNA significantly reduced the maximal relaxation to 39.7% ± 3.7% (p = 0.0007 compared with the control by Scheffé's test) (Fig 1).

View larger version (26K): [in this window] [in a new window]   Fig 1. . Mean concentration (-log M)–relaxation (percent of contraction by K+ 25 mmol/L) curves for substance P. Symbols represent data averaged from a group of rings. Vertical bars are 1 standard error of the mean of the response at each concentration. (• = control [n = 10]; = indomethacin [Indo] [n = 6]; = Indo + LNNA [n = 6], in presence of Indo [7 µmol/L] and L-NNA [300 µmol/L]; = Indo + glybenclamide [GBM] [n = 6], in presence of Indo [7 µmol/L] and GBM [3 µmol/L]; E = endothelium-denuded [n = 4].)

View larger version (13K): [in this window] [in a new window]   Fig 2. . Mean concentration (-log M)–relaxation (percent of contraction by K+ 25 mmol/L) curves for substance P. (a) When the endothelium-derived nitric oxide and the cyclooxygenase pathway was blocked (• = indomethacin [Indo] + LNNA, n = 5), the residual relaxation is related to the endothelium-derived hyperpolarizing factor mechanism and this was abolished by the exposure to hyperkalemia ( = K20/Indo + LNNA, n = 6, after incubation with 20 mmol/L K+ for 1 hour). (b) In contrast, with glybenclamide (GBM) but not L-NNA, incubation with 20 mmol/L K+ for 1 hour ( = K20/Indo + GBM, n = 6) did not reduce the relaxation of the control (• = Indo + GBM, n = 6) See Figure 1 for the dose of L-NNA and GBM.

View larger version (13K): [in this window] [in a new window]   Fig 3. . Similar effects were also seen in coronary arteries incubated with 50 mmol/L K+. See Figure 2 for the details. Symbols represent the same meaning and each group has the same number of arteries as in Figure 2. (GBM = glybenclamide; Indo = indomethacin; K50 = incubation with 50 mmol/L K+ for 1 hour.)

In endothelium-denuded rings (n = 4), SP did not induce any relaxation. This confirms that the SP-induced relaxations observed in the present study were endothelium-dependent (Fig 1). Subsequently, these rings were relaxed by nitroglycerin (-4.5 log M) to nearly full range (more than 80%) (data not shown).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The present study has demonstrated that indomethacin- and L-NNA-resistant endothelium-dependent relaxation is reduced by exposure to hyperkalemia in the porcine coronary artery. Our study may reveal a new mechanism for coronary dysfunction after exposure to cardioplegia. Because hyperkalemic solutions are widely used for organ preservation and for cardioplegia during open heart operations, this finding has strong clinical implications.

Methodology
In the present study, the porcine coronary arteries were set up at the optimal point of their own length–tension curve. This allows comparative studies among vascular rings and allows the in vitro experiments to be performed under physiologic pressure as described previously [14]. During the experiment, the coronary rings were continuously aerated by 95% O₂ and 5% CO₂ to exclude the effect of ischemia.

Effect of Hyperkalemia on Nonindomethacin and Non–L-NNA-sensitive, Endothelium-dependent Relaxation
Because the other two major components of the endothelium-dependent relaxation-the cyclooxygenase and EDNO pathways-were blocked by indomethacin and L-NNA, the residual relaxation is through the noncyclooxygenase and non-EDNO mechanism (ie, related to the effect of EDHF). In the porcine coronary artery, EDHF plays a role in the endothelium-dependent relaxation. This is reflected by the observation in the present study that in the control rings the treatment with indomethacin and L-NNA did not completely inhibit the SP-induced relaxation. The residual relaxation (39.7%) is related to the third component, the EDHF-related relaxation.

After exposure to hyperkalemia for 1 hour, the residual (indomethacin- and L-NNA–resistant) relaxation is significantly reduced and this demonstrates that the noncyclooxygenase and non-EDNO mediated relaxation is affected by the exposure. In contrast, the present study demonstrated that the EDNO-related relaxation is not altered by the exposure to hyperkalemia. In fact, in our previous study [3], it was demonstrated that when the cyclooxygenase pathway is blocked, the endothelium-dependent relaxation (related to both EDNO and EDHF pathways) is not affected by the exposure to the hyperkalemia. In the present study, we further demonstrated that in indomethacin and GBM-treated rings, exposure to hyperkalemia, in contrast to the nonindomethacin- and non–L-NNA–sensitive relaxation, did not alter the maximal response of the indomethacin- and GBM-resistant relaxation. In fact, the sensitivity to SP in the indomethacin- and GBM-treated rings after exposure to hyperkalemia was increased (EC₅₀ decreased), and this may be related to the tendency of lower precontraction in those rings, as a lower precontraction force facilitates relaxation. When the prostacyclin pathway and the adenosine triphosphate-sensitive K⁺ channels (related to the EDHF) are blocked, the EDNO pathway is not affected by the exposure to hyperkalemia. Therefore, our results demonstrate that hyperkalemia alters the noncyclooxygenase- and non–EDNO-mediated but not the EDNO-mediated endothelium-dependent relaxation. A possible explanation for this phenomenon is that hyperkalemia depolarizes the membrane and therefore, membrane hyperpolarization, in response to EDHF, becomes more difficult. Although the wash-out procedure restored the resting force of the vessel, it might be still partially depolarized, but not to the point where the vessel shows active tone before activation with the depolarizing agent. However, further studies are required to test such a hypothesis.

Potassium channels are usually subdivided according to their mode of activation [17]. It is still controversial which subtype of K⁺ channels is involved in the mechanism of EDHF. The involvement of the subtype of K⁺ channels is probably species and agonist dependent [6]. Adenosine triphosphate–sensitive K⁺ channels have been suggested to be involved in the hyperpolarization of smooth muscle by EDHF [11, 12]. In rabbit cerebral arteries, the effect of EDHF induced by acetylcholine may be inhibited by the adenosine triphosphate-sensitive K⁺ channel blocker GBM. However, in the guinea pig coronary artery, acetylcholine-induced hyperpolarization is inhibited by the Ca²⁺-activated K⁺-channel blocker tetraethylammonium chloride but not by GBM [11]. However, the hyperpolarization induced by pinacidil is inhibited by GBM, but not tetraethylammonium chloride [11]. Based on the aforementioned, in our experiments we used one of the K⁺-channel blockers, the adenosine triphosphate–sensitive K⁺-channel blocker GBM.

Effect of Hyperkalemia and the Concentration of Potassium
As to the concentration of potassium, the present study demonstrates that at least at the concentrations of 20 and 50 mmol/L, the altered noncyclooxygenase and non–EDNO-mediated relaxation is not K⁺ dose dependent. Indeed, there was no difference with regard to the magnitude of the reduction of the noncyclooxygenase and non–EDNO-mediated relaxation between the treatment with 20 and 50 mmol/L K⁺.

Clinical Significance of the Findings
It has been controversial whether hyperkalemic solutions without ischemia affect the coronary circulation. As mentioned before, in the perfused heart studies [1], the coronary flow is reduced after exposure to hyperkalemic solutions. However, the studies on isolated coronary arteries and other vessels have shown that the EDNO-mediated relaxation is unlikely altered by the exposure. The findings in the present study may fill the gap between the studies on the perfused heart and that on the isolated coronary artery. It is possible that the observations in the perfused heart studies that coronary flow is reduced after the exposure to hyperkalemic cardioplegia is attributable to alteration of the EDHF-mediated relaxation.

The direct influence of the alteration of EDHF-mediated relaxation in the coronary circulation on myocardial perfusion is still unknown. However, it is possible that if both EDNO and EDHF are active in maintaining the tone of the coronary circulation, then the present study has proposed a new mechanism for coronary dysfunction after exposure to hyperkalemic cardioplegia. When the EDHF-mediated relaxation is reduced, the artery may have a tendency to contract and this may lead to coronary dysfunction that could be critical in myocardial perfusion.

In addition, hyperkalemic solutions, such as the University of Wisconsin solution (containing potassium as high as 140 mmol/L), or Euro-Collins solution (containing 115 mmol/L of potassium) have been widely used to preserve organs (heart, lung, and others) [18–23]. Therefore, our findings also have implications in organ transplantation. Hyperkalemic organ preservation solutions may also reduce the vasorelaxant effect of EDHF during preservation.

The limitation of the present study is that from our study it is unknown whether the influence of hyperkalemia on the effect of EDHF is temporary. This will be addressed in future studies. However, at the least this effect exists immediately after the exposure to hyperkalemia that is directly related to reperfusion. This period is critical for the recovery of the heart or other organs after exposure to hyperkalemia.

To better understand the endothelium-dependent relaxation and the influence of hyperkalemia on this relaxation, we have illustrated the mechanism of the relaxation and the effect of hyperkalemia in Figure 4. In response to the increase of the intracellular (cytosolic free) calcium level, endothelial cells derive three major endothelium-derived relaxing factors. They are prostacyclin, EDNO, and EDHF. These endothelium-derived relaxing factors decrease the intracellular calcium concentration in the smooth muscle cell through different mechanisms and ultimately relax the smooth muscle cell. Prostacyclin relaxes the cell through the cyclic adenosine monophosphate pathway, whereas EDNO relaxes through the cyclic guanosine monophosphate pathway. In contrast, EDHF hyperpolarizes the cellular membrane of the smooth muscle through K⁺ channels or the Na⁺ - K⁺ pump. Subsequently this affects the calcium channels, decreases the intracellular calcium concentration, and relaxes the muscle. Exposure to hyperkalemia does not affect the EDNO pathway, probably not the prostacyclin pathway either. However, it reduces the EDHF-mediated relaxation, probably through depolarizing the membrane or affecting K⁺ channels. When the EDHF-mediated relaxation is reduced, the coronary artery may tend to contract because the balance between the contraction and the relaxation on the coronary vascular tone is altered. In particular, if the EDNO mechanism is altered by ischemia [24], the effect of hyperkalemia may superimpose to the alteration of the endothelial function.

View larger version (23K): [in this window] [in a new window]   Fig 4. . Schematic diagram describing the possible pathway by which hyperkalemia may affect coronary circulation. In response to the increase of the intracellular (cytosolic free) calcium level, endothelial cells derive three major endothelium-derived relaxing factors (EDRFs): prostacyclin (PGI2), endothelium-derived nitric oxide (EDNO), and endothelium-derived hyperpolarizing factor (EDHF). These EDRFs decrease the intracellular calcium concentration in the smooth muscle cell through different mechanisms and ultimately relax the smooth muscle cell. Exposure to hyperkalemia reduces the EDHF-mediated relaxation probably through depolarizing the membrane or affecting K+ channels. When the EDHF-mediated relaxation is reduced, the coronary artery may tend to contract because the balance between the contraction and the relaxation on the coronary vascular tone is altered. (cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate.)

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by Committee of Research and Conference grant 337/048/0018 and Vice-Chancellor grant SN/mp/350/172/0/9, University of Hong Kong.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Prof He, Division of Cardiothoracic Surgery, University of Hong Kong at The Grantham Hospital, 125 Wong Chuk Hang Rd, Aberdeen, Hong Kong.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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				G.-W. He, C.-Q. Yang, and J.-A. Yang DEPOLARIZING CARDIAC ARREST AND ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR-MEDIATED HYPERPOLARIZATION AND RELAXATION IN CORONARY ARTERIES: THE EFFECT AND MECHANISM J. Thorac. Cardiovasc. Surg., May 1, 1997; 113(5): 932 - 941. [Abstract] [Full Text]

				G.-W. He and C.-Q. Yang Radial Artery Has Higher Receptor-Mediated Contractility but Similar Endothelial Function Compared With Mammary Artery Ann. Thorac. Surg., May 1, 1997; 63(5): 1346 - 1352. [Abstract] [Full Text]

				J.-A. Yang and G.-W. He Surgical Preparation Abolishes Endothelium-Derived Hyperpolarizing Factor-Mediated Hyperpolarization in the Human Saphenous Vein Ann. Thorac. Surg., February 1, 1997; 63(2): 429 - 433. [Abstract] [Full Text]

				G.-W. He Hyperkalemia Exposure Impairs EDHF-Mediated Endothelial Function in the Human Coronary Artery Ann. Thorac. Surg., January 1, 1997; 63(1): 84 - 87. [Abstract] [Full Text]

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