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J Thorac Cardiovasc Surg 1997;114:643-650
© 1997 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

SUPERIORITY OF HYPERPOLARIZING TO DEPOLARIZING CARDIOPLEGIA IN PROTECTION OF CORONARY ENDOTHELIAL FUNCTION

Supported by Committee of Research and Conference Grant (337/048/0018, 335/048/0079), University Grant (344/048/0001), and Vice-Chancellor Grant (SN/mp/350/172/0/9), University of Hong Kong.

Received for publication Oct. 14, 1996 revisions requested Jan. 30, 1997; revisions received Feb. 19, 1997 accepted for publication March 7, 1997. Address for reprints: Professor Guo-Wei He, MD, PhD, Chair of Cardiothoracic Surgery, University of Hong Kong, The Grantham Hospital, 125 Wong Chuk Hang Rd., Aberdeen, Hong Kong.

Abstract

Objective: Hyperpolarizing cardioplegia has recently been proposed for myocardial protection. To compare the protective effect of hyperpolarizing cardioplegia and depolarizing (hyperkalemic) cardioplegia on coronary endothelium, we studied porcine coronary arteries in the organ chamber. Methods: Relaxation mediated by the endothelium-derived hyperpolarizing factor (EDHF) was used as the index of endothelial function because (1) hyperkalemia without ischemia does not impair the nitric oxide–mediated function according to previous studies and (2) EDHF relaxes vessels by hyperpolarizing the membrane potential. Therefore depolarizing cardioplegia may inhibit this function, but hyperpolarizing cardioplegia may preserve it. EDHF-mediated relaxation was induced by bradykinin and the calcium ionophore A23187 with the presence of indomethacin (7 µmol/L; INN: indometacin), a cyclooxygenase inhibitor, and N ^G-nitro-L-arginine (300 µmol), a nitric oxide biosynthesis inhibitor in U46619 (30 nmol/L)-induced precontraction. The vessels were exposed to either hyperpolarizing cardioplegic solution (the potassium-channel opener aprikalim, 0.1 mmol/L) or depolarizing cardioplegic solution (high potassium concentration, 20 mmol/L for A23187 and 50 mmol/L for bradykinin experiments) for 1 hour with a constant supply of oxygen to exclude the effect of ischemia. Results: EDHF-mediated relaxation was significantly impaired in either A23187 or bradykinin studies (80.1% ± 7.5% vs 24.9% ± 14.2%, p = 0.004, n = 8 in each group for A23187, and 71.4% ± 4.7%, n = 13, vs 40.5% ± 12.9%, n = 7, p = 0.01, for bradykinin). The effective concentration causing 50% of maximal relaxation was significantly increased in the A23187 experiments with the treatment of hyperkalemia. In contrast, in aprikalim-treated arteries, the EDHF-mediated relaxation induced by either A23187 or bradykinin was unchanged. Conclusions: We conclude that EDHF-mediated coronary endothelial function is maximally preserved by hyperpolarizing cardioplegia but impaired by depolarizing cardioplegia. These findings support the use of hyperpolarizing cardioplegia in cardiac operations.

Depolarizing cardioplegia is the most common method for myocardial preservation in cardiac operations. ¹ Potassium at high concentrations (hy-perkalemia, usually a potassium concentration of 10 to 20 mmol/L) is the major depolarizing agent in cardioplegic solutions. Despite the cardioprotective effect, depolarizing cardioplegia causes depolarization of the membrane potential by extracellular hyperkalemia, resulting in depletion of energy stores and calcium overload. ² Depolarization of the membrane is associated with an ongoing cellular metabolic process and derangements in transmembrane ionic gradients. ² It is also associated with influx of sodium through the sodium "window current," exchange of intracellular sodium for calcium via the sodium-calcium exchange, influx of calcium through the calcium "window current," ³ and leakage of calcium from the sarcoplasmic reticulum. These factors contribute to myocardial calcium overload, which is related to myocardial injury during the arrest.

As a result of these considerations, hyperpolarizing cardioplegia has been proposed to induce cardiac arrest during cardiac operations. ^2,4 The natural resting state of the cardiac myocyte is at hyperpolarized membrane potentials. ² Few channels or pumps are activated at hyperpolarized potentials, and metabolic demand on the ventricular myocyte is minimal at this status.

Potassium-channel openers have been suggested as a means of cardiac protection. ^2,4,5 Adenosine triphosphate (ATP)-sensitive potassium-channel openers inhibit the development of myocardial contracture, reduce the release of lactate dehydrogenase, and preserve intracellular ATP content during ischemia. ^6,7 Therefore use of potassium-channel openers for cardioplegia is a potential method for cardiac protection during cardiac operations. Because of the hyperpolarizing effect of potassium-channel openers on the membrane potential of myocytes, cardioplegia using potassium-channel openers 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

The effect of potassium-channel openers on the heart includes two aspects: their effect on myocytes and their effect on the coronary circulation. Theoretically, in addition to the cardioprotective effect on the myocytes, the vasorelaxant action of potassium-channel openers may provide another important benefit to 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. ^8,9 The coronary vasodilatation obviously facilitates myocardial perfusion during the reperfusion period.

During arrest of the heart, the cardioplegic solution directly contacts the coronary vascular endothelium. Therefore an important question is whether exposure to cardioplegic solution alters endothelial function. Although the effect of cardioplegia on coronary endothelial function has been studied, to date the effect of hyperpolarizing cardioplegia has not been reported.

Endothelium-dependent relaxation is known to be due to a variety of different endothelium-derived relaxing factors (EDRFs). These are endothelium-derived nitric oxide (EDNO), epoprostenol (prostacyclin [PGI₂]), and endothelium-derived hyperpolarizing factor (EDHF). The nature of EDHF has not been conclusively identified, although most recently the cytochrome P450-monooxygenase metabolite of arachidonic acid has been suggested to be EDHF. ^10,11 EDHF induces vascular smooth muscle relaxation by hyperpolarization of the smooth muscle cells, ^12-19 which may involve potassium channels. ^15,17,19,20 In contrast, EDNO mainly relaxes blood vessels through the cyclic guanosine monophosphate pathway. All of these EDRFs are released in response to the increase of intracellular (cytosolic free) calcium concentration in the endothelial cell. ¹⁹

Our previous studies ^19,21 have demonstrated that when EDNO and PGI₂ pathways are inhibited, endothelium-dependent relaxation is still significant, obviously as a result of the effect of the third component, EDHF. The studies also demonstrated that in porcine coronary arteries precontracted with the depolarizing agent potassium ²¹ or U46619, ¹⁹ this residual relaxation mediated by EDHF is significantly reduced by exposure to hyperkalemia (a potassium concentration of 20 to 50 mmol/L). We have recently demonstrated that exposure to hyperkalemia alters the EDHF-related coronary vasorelaxant effect by prolonging the depolarization, affecting the calcium-activated ¹⁹ potassium channels, and to a lesser extent affecting the ATP-sensitive potassium channels. Theoretically, hyperpolarizing arrest may preserve the EDHF-related vasorelaxant function because both potassium-channel openers and EDHF relax blood vessels through hyperpolarization of the smooth muscle membrane potential.

The present study was designed to compare the effect of hyperpolarizing cardioplegia and the effect of depolarizing cardioplegia on EDHF-related coronary endothelium–smooth muscle interaction in porcine coronary arteries. The potassium-channel opener aprikalim was used as the hyperpolarizing agent. A non-receptor-mediated (A23187) and a receptor-mediated (bradykinin) EDHF agonist was used in the present study.

Materials and methods

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 ^23,24 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% oxygen and 5% carbon dioxide at 37° C. Six organ chamber arrangements were run concurrently.

A previously described organ chamber technique ²² 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 2.1 by Yang-Hui He, Princeton University, Princeton, N.J.).

The endothelium was intentionally preserved by cautiously dissecting and mounting the rings. ^19,23-25 To examine the endothelium dependence on the relaxation to A23187 or bradykinin (n = 4 in each group), in some rings we removed the endothelium mechanically by using a fine wood stick moistened with Krebs solution to gently rub the intima of the rings. This method is able to eliminate the endothelium-dependent relaxation in the porcine coronary artery. ^19,21 In endothelium-denuded rings, nitroglycerin (-4.5 log M) 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. ^23,24

Protocol.
All rings were equilibrated for 30 minutes before and after normalization.

The effect of aprikalim or potassium on the coronary tone.
At resting status, a group of coronary rings were incubated with either aprikalim (–4 log M) added in the Krebs solution or the depolarizing agent potassium (20 mmol/L, replacing sodium) for 1 hour. The coronary artery tension was continuously recorded.

The effect of aprikalim or potassium on the EDHF-mediated relaxation.
Coronary artery rings were exposed to aprikalim (–4 log M) for 1 hour. The rings were then repeatedly washed for 30 minutes. Indomethacin (7 µmol/L; INN: indometacin), a cyclooxygenase inhibitor, and N ^G-nitro-L-arginine (L-NNA, 300 µmol/L), a nitric oxide biosynthesis/release inhibitor, were added for 30 minutes. U46619 (30 nmol/L) was then added to contract the artery. When the contraction reached the plateau, the concentration-relaxation curve to A23187 or bradykinin (-10 to -6.5 log M) was established. The group data were compared with data from the control rings (without aprikalim treatment).

A similar protocol was used for the depolarizing cardioplegia (20 mmol/L concentration of potassium in Krebs solution, replacing sodium in A23187 experiments, and 50 mmol/L concentration of potassium in bradykinin experiments).

Indomethacin and L-NNA were added 30 minutes before the concentration-relaxation curves for A23187 and bradykinin were started. 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% oxygen and 5% carbon dioxide 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 estimated 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. ^21,22 From this 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 Scheffe's test) or by the unpaired t test; p < 0.05 was considered significant.

Drugs.
Drugs used and their sources were as follows: A23187, bradykinin, L-NNA, and indomethacin (Sigma Chemical Co., St. Louis, Mo.) and U46619 (Cayman Chemical Co., Ann Arbor, Mich.). 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.

Results

Basal tone during incubation with potassium or aprikalim.
A significant difference with regard to vascular tone during incubation was noted between the potassium and aprikalim groups. In aprikalim-incubated rings, the tone significantly decreased (–6.3 ± 1.3 gm). In contrast, the tone significantly increased in the rings incubated with potassium (11.6 ± 2.5 gm, p < 0.001) (Fig. 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Coronary vascular tone during exposure to depolarization (potassium 20 mmol/L, K20) and hyperpolarization (aprikalim 100 µmol/L, APK –4). The depolarizing cardioplegic solution significantly contracted the coronary artery, but the hyperpolarizing solution relaxed the artery. n = 8 in each group.

View larger version (36K): [in this window] [in a new window]   Fig. 2. Mean concentration (–log M)–relaxation (percentage of contraction by U46619 30 nmol/L) curves for EDHF-mediated relaxation induced by A23187 in the coronary arteries exposed to depolarization (potassium 20 mmol/L [K20], A) or hyperpolarization (aprikalim 100 µmol/L [APK –4], B) for 1 hour. The experiments were performed in the presence of indomethacin (7 µmol/L), a cyclooxygenase inhibitor, and L-NNA (300 µmol/L), a nitric oxide biosynthesis/release inhibitor. n = 8 in each group. E-, Endothelium-denuded arteries (n = 4). **p < 0.01.

View larger version (42K): [in this window] [in a new window]   Fig. 3. Mean concentration (–log M)–relaxation (percentage of contraction by U46619 30 nmol/L) curves for EDHF-mediated relaxation induced by bradykinin in the coronary arteries exposed to depolarization (potassium 50 mmol/L [K50], n = 7 vs n = 13 in the control group; A) or hyperpolarization (aprikalim 100 µmol/L, APK -4, n = 7 vs n = 7 in the control group; B) for 1 hour. The experiments were performed in the presence of indomethacin (7 µmol/L) and L-NNA, 300 µmol/L. E-, Endothelium-denuded arteries (n = 4). *p < 0.05.

Bradykinin-induced relaxation.
Bradykinin-induced relaxation was 69.8% ± 10.5% (n = 7) in the control rings and 68.3% ± 5.9% in the aprikalim-incubated rings (n = 7, p = 0.9) (Fig. 3, B).

In A23187-induced relaxation, the EC₅₀ was similar in the control and the aprikalim-treated arteries (-7.21 ± 0.02 vs -7.24 ± 0.13 log M, p = 0.7). In bradykinin experiments, the relaxation was slightly potentiated in the arteries treated with aprikalim (–8.20 ± 0.07 vs –7.77 ± 0.11 log M in the control rings, p = 0.03) (Table II).

In endothelium-denuded rings, neither A23187 nor bradykinin induced any relaxation, a fact which confirms that the relaxations observed in the present study were endothelium-dependent (Figs. 2 and 3).

Discussion

The present study has demonstrated for the first time that hyperpolarizing arrest may be superior to depolarizing arrest with regard to the preservation of EDHF-related endothelium–smooth muscle interaction and, therefore, may provide better protection to the coronary circulation and the heart.

The role of EDHF in the coronary circulation.
EDHF has been suggested to play a role in coronary arteries. ^19,20,26,27 In the present study we found that when the other two components of EDRFs—EDNO and PGI₂—were inhibited, both A23187 and bradykinin induced more than 70% relaxation, and this residual relaxation is still endothelium-dependent. This observation is consistent with findings from our previous studies, ^19,21 which demonstrate that EDHF is one of the active EDRFs in the coronary circulation. Most recently, we have shown that this activity is also present in the human coronary circulation. ²⁸ Therefore "perfect" cardiac protection should include the preservation of this component of endothelial function.

Effect of hyperpolarizing cardioplegia on vascular tone.
Use of hyperpolarizing instead of depolarizing cardioplegia is a recent suggestion for myocardial protection. ^2,4 However, such studies are still in the animal experimentation stage. It has been suggested that hyperpolarizing cardioplegia may have advantages over depolarizing cardioplegia in terms of protecting the myocardium. ^2,4 However, the effect of hyperpolarizing cardioplegia on the coronary circulation has not been studied. Theoretically, in contrast to depolarizing cardioplegia, which may contract the coronary arteries because of the high potassium concentration, hyperpolarizing cardioplegia using vasodilators (potassium-channel openers) has a vasorelaxant effect. This effect is well demonstrated in the present study. When the coronary arteries were incubated with aprikalim, the basal tone decreased to –6.3 gm, and this showed an excellent vasorelaxant effect of this potassium-channel opener in the coronary circulation as demonstrated in other vessels. ²⁹ In contrast, when the arteries were incubated with a 20 mmol/L concentration of potassium, the tone increased to 11.6 gm owing to the vasoconstrictor effect of potassium.

EDHF-related relaxation and depolarizing/hyperpolarizing cardioplegia.
In our studies, other two major components of endothelium-dependent relaxation—the cyclooxygenase and EDNO pathways—were blocked by indomethacin and L-NNA. Therefore the residual relaxation is obviously through the non-cyclooxygenase and non-EDNO mechanism, that is, related to the effect of EDHF.

As shown in our studies, EDHF-mediated relaxation was reduced to 24.9% in A23187-induced relaxation and to 40.5% in bradykinin-induced relaxation. Taken together with the results from the previous study, ²¹ our data suggest that the reduction of the residual relaxation by hyperkalemia is not agonist-dependent. Therefore this effect is a uniform phenomenon affecting the coronary endothelium—smooth muscle interaction.

In the current study, we used a 20 mmol/L concentration of potassium as the depolarizing agent because this is a concentration used in cardioplegic solutions by various institutions (such as St. Vincent Hospital, Portland). In addition, although the theoretic concentration of potassium in St. Thomas' Hospital cardioplegic solution is 16 mmol/L, in clinical practice it varies between 16 and 21 mmol/L, as we measured daily when this solution was prepared during surgery in the operating room. With regard to higher concentrations of potassium, owing to the fact that the potassium concentration is as high as 125 mmol/L in organ preservation solutions such as University of Wisconsin solution, we arbitrarily chose a moderately high concentration (50 mmol/L) to test whether the effect at 20 mmol/L still exists at higher concentrations.

As mentioned earlier, EDHF relaxes blood vessels by hyperpolarizing the smooth muscle membrane, similar to potassium-channel openers. Therefore both potassium-channel openers and EDHF relax smooth muscle by hyperpolarizing the cellular membrane of the smooth muscle, and the use of potassium-channel openers should not influence the effect of EDHF. This hypothesis is supported by the present study. In our experiments, the use of aprikalim did not affect subsequent EDHF-mediated relaxation induced by either A23187 or bradykinin.

In our experiments, EDHF-mediated function was not tested during exposure to cardioplegic solution. In fact, it was measured after the repeated wash of the cardioplegic solution for at least half an hour, as in the previous studies. ^19,21 This period simulates the "reperfusion" period. The results from the present study suggest that the inhibitory effect of the depolarizing but not the hyperpolarizing cardioplegic solution on EDHF-mediated relaxation lasts for at least half an hour after washout and therefore still exists during the "reperfusion" period.

In summary, our experiments suggest that one of the coronary endothelial functions, EDHF-mediated relaxation, is impaired by depolarizing cardioplegia but preserved by hyperpolarizing cardioplegia. Fig. 4 illustrates the mechanism of this effect. Depolarizing cardioplegia reduces EDHF-mediated relaxation by depolarizing the membrane and possibly also by affecting potassium channels. In contrast, hyperpolarizing cardioplegia with potassium-channel openers hyperpolarizes the membrane potential and therefore is synergistic to the effect of EDHF.

View larger version (19K): [in this window] [in a new window]   Fig. 4. Schematic diagram describing the possible pathway by which depolarizing (hyperkalemia) and hyperpolarizing (aprikalim) may affect the interaction between endothelium and smooth muscle. In response to the increase of the intracellular (cytosolic free) calcium level, endothelial cells derive three major EDRFs (PGI2, EDNO, and EDHF). These EDRFs decrease the intracellular calcium concentration in the smooth muscle cell through different mechanisms and ultimately relax the smooth muscle cell. The mechanism of EDHF to relax vessels is to open potassium channels and hyperpolarize the membrane. Subsequently, the voltage-operated calcium (Ca2+) channels are inhibited and therefore the calcium influx is reduced, and this causes relaxation. Use of hyperpolarizing cardioplegia may enhance this function because both potassium-channel openers (KCO) and EDHF relax the vessel by hyperpolarizing the membrane. In contrast, exposure to depolarizing cardioplegia (hyperkalemia) reduces the EDHF-mediated relaxation by affecting potassium channels and prolonged depolarization.

We conclude that depolarizing arrest (exposure to hyperkalemia) reduces EDHF-mediated relaxation, but hyperpolarizing arrest (with potassium-channel openers) preserves this function of the endothelium. In addition to the previous findings that hyperpolarizing cardioplegia may effectively protect the cardiac myocytes, our study supports the use of hyperpolarizing cardioplegia in cardiac operations from the view of preserving coronary endothelial function. Further studies are warranted to test this effect in in vivo models.

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