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J Thorac Cardiovasc Surg 2002;124:361-370
© 2002 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CSP) |
From the Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China,a and Providence Heart Institute, Albert Starr Academic Center, the Department of Surgery, Oregon Health & Science University, Portland, Ore.b
Supported in full by grants from the Research Grant Council of the Hong Kong Special Administrative Region (Projects CUHK7246/99M and CUHK4127/01M), China, and the Providence St Vincent Medical Foundation, Portland, Ore.
Received for publication July 23, 2001. Revisions requested Sept 12, 2001; revisions received Dec 20, 2001. Accepted for publication Dec 27, 2001. Address for reprints: Guo-Wei He, MD, PhD, Department of Surgery, Block B, 5A, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China (E-mail: gwhe{at}cuhk.edu.hk).
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
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1 The major depolarizing agent in these cardioplegic solutions is potassium at high concentrations (hyperkalemia), usually 10 to 20 mmol/L. 1 Previous studies have shown that hyperkalemia causes damage to arterial endothelial function. 2-4
Endothelium exerts an important modulatory effect on vascular tone. Endothelium-dependent relaxation is known to be caused by a variety of endothelium-derived relaxing factors. These are endothelium-derived nitric oxide, prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF). 5,6 Because of the complexity of endothelial function, it is necessary to study the functions of individual endothelium-derived relaxing factors to find the "perfect" method to preserve the endothelium during cardiac surgery. EDHF-mediated endothelial function plays an important role in the coronary circulation as the backup for nitric oxide, particularly in the coronary microarteries. 7
On the basis of these considerations, our laboratory has demonstrated that hyperkalemia alters EDHF-mediated relaxation and hyperpolarization (the electrophysiologic basis of mechanical relaxation) in both porcine and human coronary conduit arteries. 6,8,9 Most recently, we have found that this is also true in porcine coronary microarteries. 10
Apart from potassium, magnesium is another important ion in either crystalloid 11 or blood 12,13 cardioplegia. For example, St Thomas' Hospital solution contains 16-mmol/L magnesium ion. It has been reported that addition of magnesium to the cardioplegic solution is beneficial in myocardial protection. 11 Moreover, in blood cardioplegia, magnesium ion is also suggested to be supplemented to relieve cardiac injury. 12,13 Although much is known about magnesium's favorable effect on cardiac myocytes, little is known about its effect on endothelial function. Although there is evidence that hypermagnesemic cardioplegia is superior to hyperkalemic cardioplegia in preserving endothelium-dependent relaxation in porcine coronary microvessels, 14 the effects of magnesium ion on EDHF-mediated relaxation and hyperpolarization have not been reported. We have previously observed that vascular tone increases during incubation with potassium ion at 16 to 20 mmol/L but remains almost normal during incubation with St Thomas Hospital cardioplegia. 15 We therefore hypothesized that the normal vascular tone during incubation with the St Thomas Hospital cardioplegia solution is due to the reversal effect of the magnesium ion contained in that solution and thus that magnesium ion may have a protective effect on EDHF-mediated relaxation and hyperpolarization. To test this hypothesis, this study was designed to investigate the effects of magnesium ion and its interaction with potassium ion on EDHF-mediated relaxation and hyperpolarization induced by bradykinin in porcine coronary arteries.
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Material and methods |
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During the preceding procedure, the endothelium was intentionally preserved by cautiously dissecting and mounting the rings. After the rings were mounted in a four-channel myograph (model 610A; J.P. Trading, Aarhus, Denmark), a previously described method 6,10 was used to normalize vascular rings under a condition simulating the transmural pressure encountered in vivo in the coronary microartery. Briefly, the artery rings were progressively stretched until the passive transmural pressure reached 100 mm Hg. The internal circumference was then set to a normalized value, estimated to be equivalent to 90% of the circumference at a passive transmural pressure of 100 mm Hg. This pressure was maintained throughout the experiments.
Protocols
All rings were equilibrated for 30 minutes before and after normalization. The following protocols were used.
GROUP I (N = 8 IN EACH SUBGROUP). Effect of potassium ion (20 mmol/L) or magnesium ion (16 mmol/L) on endothelium-derived hyperpolarizing factor-mediated relaxation in microarteries.
Four rings taken from the same artery were allocated into four groups. The arterial rings were incubated with four different solutions for 1 hour at 37°C: subgroup Ia, Krebs solution as a control; subgroup Ib, potassium ion (20 mmol/L); subgroup Ic, magnesium ion (16 mmol/L); and subgroup Id, potassium ion (20 mmol/L) plus magnesium ion (16 mmol/L). In these high-potassium or high-magnesium solutions, sodium was replaced with the equivalent potassium or magnesium form. In 20-mmol/L potassium ion solution, 14-mmol/L sodium chloride was replaced with 14-mmol/L potassium chloride. In 16-mmol/L magnesium ion solution, 29.6-mmol/L sodium chloride (14.8 x 2) was replaced with 14.8-mmol/L magnesium sulfate. In the combined 20-mmol/L potassium ion and 16-mmol/L magnesium ion solution, 43.6-mmol/L sodium chloride (14 + 14.8 x 2) was replaced with 14-mmol/L potassium chloride and 14.8-mmol/L magnesium sulfate. The osmolarity therefore remained unchanged.
Inhibitors for PGI2 and nitric oxide were then added into the chamber. They were as follows: indomethacin (7 µmol/L, a cyclo-oxygenase inhibitor), NG-nitro-L-arginine (L-NNA, 300 µmol/L, a nitric oxide synthase inhibitor), and oxyhemoglobin (20 µmol/L, a nitric oxide scavenger). The arteries were contracted with U46619 in varying amounts (-8.4 log mol/L for subgroup Ib, -7.5 log mol/L for subgroups Ia and Id, and -7 log mol/L for subgroup Ic) to reach a similar contraction force, because the arteries in subgroups Ib and Id were already contracted with 20-mmol/L potassium ion. Subsequently, concentration-relaxation curves were established for bradykinin (-10 to -6.5 log mol/L) in the presence of indomethacin, L-NNA, and oxyhemoglobin. This relaxation was the EDHF-mediated relaxation, because the production of both nitric oxide and PGI2 were inhibited. 7
GROUP II (N = 6 IN EACH SUBGROUP). Effect of potassium ion (20 mmol/L) or magnesium ion (16 mmol/L) on sodium nitroprusside-induced relaxation in microarteries.
Four rings taken from the same artery (subgroups IIa-IId) were incubated with different solutions as in group I. After 1 hour, sodium nitroprusside (SNP, -9 to -4 log mol/L) was cumulatively applied to induce relaxation in the arteries previously contracted with U46619 (-8.4 to -7 log mol/L, see group I).
GROUP III (N = 8 IN EACH SUBGROUP). Effect of potassium ion (20 mmol/L) or magnesium ion (16 mmol/L) on endothelium-derived hyperpolarizing factor-mediated relaxation in microarteries after washout.
The protocol was similar to that in group I. Four rings taken from the same artery were allocated into four subgroups. The arterial rings were incubated with four different solutions for 1 hour at 37°C: subgroup IIIa, Krebs solution as a control; subgroup IIIb, 20-mmol/L potassium ion; subgroup IIIc, 16-mmol/L magnesium ion; and subgroup IIId, 20-mmol/L potassium ion plus 16-mmol/L magnesium ion. In these high-potassium ion or high-magnesium ion solutions, sodium was replaced with the equivalent potassium or magnesium form as described previously. One hour later, the solutions were replaced with the normal Krebs solution, and inhibitors for PGI2 and nitric oxide were added into the chamber. The washout time was 45 minutes. The arteries were contracted with U46619 (-8.0 log mol/L). Subsequently, concentration-relaxation curves were then established for bradykinin (-10 to -6.5 log mol/L) in the presence of indomethacin, L-NNA, and oxyhemoglobin.
In another group of experiments, arterial rings (n = 8) were denuded of endothelium mechanically to examine the endothelium dependence of the bradykinin-induced relaxation.
Electrophysiological studies (cellular membrane potential measurement)
Porcine epicardial coronary arteries were dissected out, and a segment (3-4 mm) was carefully slit along the longitudinal axis. The strips were pinned down by stainless steel pins, inner side upward, on the bottom of a 2-mL organ bath. The strip of the coronary artery was superfused with Krebs solution at the rate of 2 mL/min, aerated with mixture of 95% oxygen and 5% carbon dioxide at 37°C. After 60 minutes of equilibrium, a glass microelectrode filled with 3-mol/L potassium chloride (tip resistance 40-80 M
) was inserted into a smooth muscle cell from the endothelial side. 6,7,9 The electrical signals were amplified by means of a microelectrode amplifier electrometer (ELECTRO 705; World Precision Instruments, Inc, Sarasota, Fla). The output signals were displayed on an oscilloscope (2120 B; World Precision Instruments) and recorded by a computer that installed Picoscope program (Pico Technology Limited, Hardwick, United Kingdom). The criteria of impaling cells were a sudden negative change in voltage followed by a stable negative voltage for more than 1 minute as well as an instantaneous return to the previous voltage level on dislodgment of the microelectrode. 6,7,9,16-18
Protocols
After equilibrium for 60 minutes, a microelectrode was inserted into the smooth muscle cell and the baseline (resting) membrane potential was recorded. In the presence of indomethacin (7 µmol/L) and L-NNA (300 µmol/L) for 30 minutes, concentration-response (hyperpolarization) curves were established for bradykinin (-10 to -6.5 log mol/L) as a control. The vascular strip was washed with normal Krebs solution for 30 minutes to restore the baseline (resting) membrane potential and then superfused with one of the three modified Krebs solutions containing 20-mmol/L potassium ion, 16-mmol/L magnesium ion, or 20-mmol/L potassium ion plus 16-mmol/L magnesium ion (final concentration). In these solutions, sodium was replaced with the equivalent potassium or magnesium form as described previously to maintain the final osmolarity of the solution. The protocols were as follows: subgroup IVa, superfusion with Krebs solution containing 20-mmol/L potassium ion for 1 hour; subgroup IVb, superfusion with Krebs solution containing 16-mmol/L magnesium ion for 1 hour; and subgroup IVc, superfusion with Krebs solution containing 20-mmol/L potassium ion and 16-mmol/L magnesium ion for 1 hour.
The vessel was then washed within 30 minutes, and the concentration-response (hyperpolarization) curve for bradykinin was established with the presence of indomethacin (7µmol/L) and L-NNA (300 µmol/L). Another group of coronary arterial strips were used as the time control for the bradykinin-induced hyperpolarization.
In separate experiments, coronary arteries (n = 6) were denuded of endothelium mechanically to examine the endothelium dependence of the bradykinin-induced hyperpolarization.
Data analysis
Relaxation was expressed as the percentage decrease in isometric force induced by U46619. The effective concentration of bradykinin that caused 50% of maximal relaxation was defined as the EC50. The EC50 was determined from each concentration-relaxation curve by a logistic, curve-fitting equation: E = MAP/ (AP + KP), where E is response, M is maximal relaxation, A is concentration, K is EC50, and P is the slope parameter. From this fitted equation, the mean (± SEM) EC50 was calculated for each group.
Statistical analysis
Data were expressed as mean ± SEM and were analyzed with analysis of variance (ANOVA) followed by the Scheffé F test or t test as appropriate.
Drugs
Drugs used and their sources were as follows: bradykinin, L-NNA, and indomethacin, Sigma Chemical Co (St Louis, Mo); and U46619, Cayman Chemical (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.
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Results |
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, A). However, this difference disappeared when the incubated solution was washed out (group II, P = .733; Figure 2, B).
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). These results imply that incubation with 20-mmol/L potassium ion either with or without magnesium ion significantly decreased the sensitivity of the artery to bradykinin (increased EC50). In group III, there were no differences between the control subgroup and other subgroups with respect to the EC50. In the 8 arteries with the endothelium denuded, the bradykinin-induced relaxation was abolished.
Effects of 20-mmol/L potassium ion, 16-mmol/L magnesium ion, or both on sodium nitroprusside-induced relaxation (group II)
SNP caused marked vasorelaxation in a concentration-dependent manner, and full relaxation (100%) occurred at -4 log mol/L. Incubation with either 20-mmol/L potassium ion (subgroup IIb), 16-mmol/L magnesium ion (subgroup IIc), or 20-mmol/L potassium ion plus 16-mmol/L magnesium ion (subgroup IId) did not alter the SNP-induced relaxation (97.9% ± 0.9% in subgroup IIb, 100% ± 0% in subgroup IIc, and 99.2% ± 0.8% in subgroup IId, P > .05; Figure 3, B). In addition, there were no differences in EC50 among these 4 subgroups.
Electrophysiologic studies
Membrane potential during incubation
During incubation, the membrane potential was significantly depolarized by 20-mmol/L potassium ion (-39.7 ± 1.5 vs -60.1 ± 0.5 mV, P < .001). In contrast, incubation with 16-mmol/L magnesium ion hyperpolarized the membrane potential from -60.4 ± 1.5 to -63.3 ± 1.6 mV (P = .001). Interestingly, incubation with 20-mmol/L potassium ion plus 16-mmol/L magnesium ion partially depolarized the membrane potential (-49.0 ± 1.4 vs -60.1 ± 1.5 mV, P < .001), and the magnitude of the depolarization was significantly less than that in the subgroup IVa (P < .01, Figure 5). During the washout period, the membrane potential remained slightly higher (in subgroup IVa, Figure 6, A) or returned to the previous level (in subgroups IVb and IVc, Figure 6, B and C).
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, A). The maximal change was from -72.0 ± 1.5 mV to -61.7 ± 1.5 mV (n = 7, P < .01). In contrast, superfusion with magnesium ion (subgroup IVb) did not alter the hyperpolarization (Figure 6, B). When the superfusion was 20-mmol/L potassium ion plus 16-mmol/L magnesium ion (subgroup IVc), the hyperpolarization was significantly reduced relative to the control value (-68.0 ± 2.5 mV vs -72.5 ± 1.5 mV, n = 6, P < .05; Figure 6, C). However, compared with superfusion with potassium ion 20 mmol/L alone, the change of the membrane potential was significantly recovered (10.0 ± 1.0 vs. 3.3 ± 0.8 mV, n = 7, P < .01) (Figure 6, D). Figure 5, D, also shows the comparison of the magnitude of the change of membrane potential in response to bradykinin among the subgroups of group IV. Potassium ion greatly reduced the magnitude of bradykinin-induced hyperpolarization of the membrane potential, whereas magnesium ion did not. In the 8 arteries with the endothelium denuded, the bradykinin-induced hyperpolarization was abolished. |
Discussion |
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Coronary tone during incubation with magnesium ion
In this study, the coronary microarterial tone increased when the vessel was incubated with 20-mmol/L potassium ion, a well-known phenomenon. We previously demonstrated that the coronary tone remains almost without change when the artery is incubated with St Thomas Hospital cardioplegic solution, which also contains 20-mmol/L potassium ion. The difference between the effects of these two solutions is obviously related to other components in the St Thomas Hospital solution, and we therefore became interested in investigating the effects of another main cation contained in St Thomas Hospital cardioplegic solution, 16-mmol/L magnesium ion. The effects of magnesium ion on the vascular tone may be 2-fold, on the resting force and on contracted vessels.
The inhibitory effect of magnesium ion on the potassium ion-induced increase in tone is clearly shown in Figure 1. Compared with the marked increase in tone induced by 20-mmol/L potassium ion, addition of 16-mmol/L magnesium ion completely inhibited the potassium-induced contraction. When the coronary artery was incubated with 16-mmol/L magnesium ion alone, the tone was slightly reduced relative to the control value. Thus in the coronary arteries in both resting and contracted states, the effect of 16-mmol-L magnesium ion is to reduce the tone.
It has been reported that the effects of magnesium ion on the vasculature involve a few mechanisms. Nakajima and associates 19 reported that extracellular magnesium ion inhibits receptor-mediated nonselective cation current, which may contribute to the relaxation effects in vascular smooth muscle cells. Skajaa and colleagues 20 demonstrated that magnesium ion inhibits the vascular response to several vasoconstrictors, such as potassium ion and prostaglandin F2
, through affecting transmembrane calcium influx and interfering with intracellular calcium effects. 20 Further, it has been suggested that extracellular magnesium ion at low concentrations (0.1-6 nmol/L) can promote relaxation by endothelium-derived relaxing factor and nitric oxide 21 and by cyclo-oxygenase-dependent mechanisms, such as the production of prostacyclin. 22 Because the concentration of magnesium ion was as high as 16 mmol/L, we believe that the mechanism of its inhibitory effect on contraction was related to the direct action on the vascular smooth muscle, as mentioned previously. 19,20
The membrane potential of the smooth muscle in the coronary artery during incubation with magnesium ion
In the resting state, in contrast to potassium ion, magnesium ion alone at the concentration in St Thomas Hospital cardioplegic solution (16 mmol/L) significantly decreased the membrane potential (hyperpolarization; Figure 4). Further, the addition of magnesium ion to hyperkalemic solutions reduced the depolarization caused by potassium ion alone (P = .008), although the membrane potential was still partially depolarized (Figure 4). These experiments clearly demonstrate that the effect of magnesium ion is to reduce the membrane potential either in the resting state or when the membrane is depolarized. Combined with the findings in the force recording during incubation that magnesium ion, either alone or added to the potassium ion solution, slightly reduced the resting force (Figure 1), the results clearly show that the previously found reduction of resting force during incubation with St Thomas Hospital cardioplegic solution 15 is most likely due to the magnesium ion contained in this solution. In addition, these experiments demonstrate that the mechanism of the reduced tone induced by magnesium ion is due to its relaxation-linked membrane hyperpolarization of the coronary smooth muscle cell.
Effect of magnesium ion on U46619-induced contraction
For similar reasons to those mentioned previously, the contraction induced by U46619 was significantly reduced in the magnesium ion-treated arteries. Even when the dose of U46619 was increased in an attempt to reach a similar extent of contraction for the relaxation studies with bradykinin, the contraction response to U46619 was still less than that in other groups. This effect, however, almost disappeared after washout for 45 minutes.
Effects and mechanisms of potassium ion and magnesium ion action on endothelium-derived hyperpolarizing factor–related relaxation and hyperpolarization
Effect of potassium ion on endothelium-derived hyperpolarizing factor-related relaxation and hyperpolarization
After incubation with 20-mmol/L potassium ion for 1 hour, the EDHF-mediated relaxation and hyperpolarization induced by bradykinin were significantly reduced. These results are consistent with our previous studies, which demonstrated that EDHF-mediated response was impaired by hyperkalemia. 6,8-10 The mechanism of the impairment may involve prolonged membrane depolarization and altered activity of the calcium-activated potassium channels. 6,8 The effect of 20-mmol/L potassium ion on the hyperpolarization induced by bradykinin was demonstrated in this study. The membrane potential was greatly increased (depolarization) in the coronary artery and the bradykinin-induced hyperpolarization was also greatly reduced (Figure 5). The change in this relaxation-linked hyperpolarization further reveals the mechanism of the hyperkalemia-induced reduction of the EDHF-mediated function.
Effect of magnesium ion on endothelium-derived hyperpolarizing factor-related relaxation and hyperpolarization
In contrast, incubation with magnesium ion did not significantly alter either the relaxation or the hyperpolarization induced by bradykinin (Figures 3 and 5, B). These results clearly show that the addition of magnesium ion in a physiologic solution completely preserves EDHF-mediated endothelial function. This is already a favorable effect. More important, addition of magnesium ion to a hyperkalemic cardioplegic solution can reduce the impairment of the EDHF-mediated function. When the artery was incubated with potassium ion plus magnesium ion, the bradykinin-induced EDHF-mediated relaxation was partially preserved relative to that in the arteries incubated with potassium ion alone (Figure 3, A). This partial recovery in the EDHF-mediated endothelial function was due to the protective effect of magnesium ion on the EDHF function, because the membrane hyperpolarization induced by bradykinin after incubation with potassium ion plus magnesium ion was significantly more than that in arteries incubated with potassium ion alone (P < .01, Figure 6, A, C, and D). As previously demonstrated, hyperkalemia impairs EDHF-mediated relaxation by depolarizing the membrane and inhibiting the calcium-activated potassium channels. 6,8-10 Taken together, the effects of potassium ion and magnesium ion on the membrane potential result in a favorable effect of magnesium ion when added to the hyperkalemic solution. Figure 6 depicts the effects of both potassium ion and magnesium ion on the membrane potential of the coronary smooth muscle cell regarding the EDHF-mediated endothelial function and shows the possible mechanisms of action.
This study therefore demonstrated that the restoration of the relaxation-linked hyperpolarization of the membrane potential of coronary smooth muscle cells by magnesium ion is the mechanism of the protective effect of the EDHF-mediated relaxation by magnesium ion. This finding further supports the use of magnesium ion in cardioplegic solutions.
Limitations of the study
This study addressed an important consideration in cardioplegic arrest regarding the effect of magnesium ion. However, the study was an in vitro experimental investigation. The effect of reduced sodium in the experiment (to exclude the effect of changed osmolarity) is unknown. In addition, the overall effect of the alteration of the EDHF-mediated relaxation after cardioplegic arrest on the coronary flow remains to be studied further.
Clinical implications
Magnesium ion has been shown to have a cardioprotective effect against ischemia-reperfusion injury. 13,23-27 This study demonstrated that magnesium ion alone completely preserves EDHF-mediated endothelial function, and when added to hyperkalemic cardioplegia it allows significant recovery of the EDHF-mediated endothelial function impaired by the high potassium ion concentration. Therefore this study provides strong evidence that supplementation of magnesium ion in hyperkalemic cardioplegia is essential for endothelial protection.
In conclusion, magnesium ion alone preserved EDHF-mediated relaxation and hyperpolarization in porcine coronary microarteries in vitro. When added to hyperkalemic cardioplegia, magnesium ion significantly restored the EDHF-mediated endothelial function impaired by hyperkalemia. The mechanism of the protective effect of magnesium ion is related to the preservation of the membrane hyperpolarization and the reversal of the potassium ion-induced depolarization of the smooth muscle cell. Thus this study strongly supports the use of magnesium ion in cardioplegic solutions.
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