| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 1997;113:932-941
© 1997 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Supported by a Committee of Research and Conference Grant (337/048/0018) and a Vice-Chancellor Grant (SN/mp/350/172/0/9), University of Hong Kong.
Received for publication March 21, 1996 revisions requested May 23, 1996; revisions received August 12, 1996 accepted for publication August 12, 1996. 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
Objectives: Depolarizing (hyperkalemic) solutions are widely used to preserve organs for transplantation and for cardiac operations. We previously observed that exposure to hyperkalemia reduced endothelium-dependent, noncyclooxygenase- and non–nitric oxide–mediated relaxation. This study was designed to examine the mechanism of this effect with regard to K channels and the associated membrane potential changes.Methods: Porcine coronary artery rings were studied in organ chambers. After incubation of the tissue with 20 or 50 mmol/L doses of potassium for 1 hour, the endothelium-derived hyperpolarizing factor–mediated relaxation in the artery and the membrane hyperpolarization in a single coronary smooth muscle cell were studied.Results: The endothelium-derived hyperpolarizing factor–mediated relaxation induced by substance P, which could be significantly inhibited by the Ca2+-activated K channel blocker tetraethylammonium but only to a lesser extent by the adenosine triphosphate–sensitive K channel blocker glibenclamide, was significantly reduced. Substance P–induced hyperpolarization of the membrane potential was also significantly reduced by the hyperkalemic incubation with a significantly elevated resting membrane potential.Conclusions: Depolarizing arrest reduces endothelium-derived hyperpolarizing factor–mediated membrane hyperpolarization and relaxation by affecting mainly the Ca2+-activated K channels and by depolarizing the membrane for a prolonged period. We suggest that this is one of the mechanisms for coronary dysfunction after exposure to depolarizing (hyperkalemic) cardioplegic and organ-preservation solutions and that, therefore, "perfect" protection of the heart or other organs should restore the endothelium-derived hyperpolarizing factor–related endothelial function.
Depolarizing cardioplegia is the most common method for myocardial preservation in cardiac operations. Potassium (K) at high concentrations (hyperkalemia) is the major depolarizing agent in cardioplegic solutions (usually containing a 10 to 20 mmol/L concentration of K). In addition, hyperkalemia is also a key component in organ-preservation solutions for transplantation such as in the University of Wisconsin solution (containing a 125 mmol/L concentration of K). During arrest of the heart or the preservation period of the donor organ, the hyperkalemic solution directly contacts the vascular endothelium. The effect of cardioplegic and organ-preservation solutions on endothelium has, therefore, been the focus of investigators in several recent studies.
1-5
Despite reports regarding the detrimental effect of cardioplegic solutions on the coronary endothelium, 1,5 studies have suggested that crystalloid cardioplegic solution does not impair endothelium-dependent relaxation. 2 We further demonstrated that the noncyclooxygenase pathway–mediated endothelium-dependent relaxation in porcine coronary arteries 3 and neonatal rabbit aortas 4 is not altered by exposure to hyperkalemia or cardioplegic solutions. However, most recently, we have discovered that endothelium-dependent relaxation mediated by the noncyclooxygenase and non–nitric oxide pathway (that is, the endothelium-derived hyperpolarizing factor [EDHF] pathway) in porcine coronary arteries is altered by exposure to hyperkalemia. 6
Endothelium-dependent relaxation is known to be the effect of a variety of different endothelium-derived relaxing factors (EDRFs). These are endothelium-derived nitric oxide (EDNO), prostacyclin (prostaglandin I2), and EDHF. In contrast to EDNO and prostaglandin I2, the nature of EDHF has not been fully identified. 7 EDHF induces vascular smooth muscle relaxation via hyperpolarization of the smooth muscle cells, 8-13 which may involve potassium (K) channels. 11-13 In contrast, EDNO relaxes blood vessels through the cyclic guanosine monophosphate pathway. 8,14 However, all of these EDRFs are released in response to the increase of intracellular (cytosolic free) calcium concentration in the endothelial cell. 7
Our previous study demonstrated that in the porcine coronary artery precontracted by the depolarizing agent K, EDHF-mediated relaxation is significantly reduced by exposure to hyperkalemia (K concentration of 20 to 50 mmol/L). 6 However, the mechanism is unknown. On the basis of the previous findings suggesting that the mechanism of EDHF is related to K channels 12-15 and that hyperpolarization of the membrane potential is the direct response of smooth muscle to EDHF, we hypothesized that the mechanism of the observed reduction of EDHF-mediated relaxation is related to inhibition of K channels and prolonged depolarization of the smooth muscle membrane potential. Fig. 1 illustrates our proposal with regard to the mechanism (explanation given in figure legend).
|
Material and methods
Isometric tension studies.
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 within 1 hour. On receipt of the heart, epicardial coronary arteries were immediately 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 with Krebs solution at 37° C. The Krebs solution had the following composition (in millimolars): Na+ 144, K+ 5.9, Ca2+ 2.5, Mg2+ 1.2, Cl- 128.7, HCO3- 25, SO42- 1.2, H2PO4- 1.2, and glucose 11. The solution was aerated with a gas mixture of 95% O2/5% CO2 at 37° C. Six organ-chamber arrangements were run concurrently. We have previously demonstrated that endothelium-dependent relaxation is well preserved by this method. 3,4,6
A previously described organ-chamber technique 16,17 was used to normalize vascular rings under physiologic pressure with use of a computer program (VESTAND 2.1 by Yang-Hui He, Princeton University).
The endothelium was intentionally preserved by cautiously dissecting and mounting the rings. 3,4,6 To examine the endothelium dependence of the relaxation to substance P (n = 4 to 7 in each group), in some rings the endothelium was removed mechanically with use of a fine wood stick moistened with Krebs solution to gently rub the intima of the rings. This method has been demonstrated to eliminate endothelium-dependent relaxation in the canine coronary artery 16 and the human internal thoracic artery. 18 In endothelium-denuded rings, nitroglycerin (-4.5 log M) was added at the end of the experiments to test whether those rings could still be relaxed with this endothelium-independent vasorelaxant agent. 3,16
The protocol of these studies was as follows. All rings were equilibrated for 30 minutes before and after normalization. U46619 (30 nmol/L) was then added to the organ chamber to contract the rings. When the contraction reached a stable plateau (usually after 10 minutes), cumulative concentration-response curves to substance P were established as follows. The concentrations for substance P were -12 to -8 log M.
Control.
The concentration-relaxation curves were established with the presence of various combinations of inhibitors as follows: (1) indomethacin (7 µmol/L), a cyclooxygenase inhibitor, and NG-nitro-L-arginine (L-NNA, 300 µmol/L), a nitric oxide biosynthesis/release inhibitor; (2) indomethacin (7 µmol/L), L-NNA (300 µmol/L), and a Ca2+-activated K channel (KCa) blocker, tetraethylammonium (1 mmol/L); (3) indomethacin (7 µmol/L), L-NNA (300 µmol/L), and an adenosine triphosphate–sensitive K channel (KATP) blocker, glibenclamide (3 µmol/L); and (4) indomethacin (7 µmol/L) and glibenclamide (3 µmol/L).
In our pilot experiments, we tested the endothelial preservation in two ways. First, we prolonged the time for the coronary preparation in the organ chamber for up to 4.5 hours with frequent washing to simulate the situation after exposure to K (n = 10). Second, in the presence of indomethacin and L-NNA, after the first relaxation curve to substance P, the rings were repeatedly washed. The same inhibitors were then added and the artery was contracted with U46619 (30 nmol/L) again. The second substance P relaxation curve was induced (n = 6). In both situations, the substance P–induced relaxation showed no difference compared with the substance P relaxation induced without waiting for 4.5 hours (in the first situation) or with the first substance P–induced relaxation (in the second situation). This demonstrated that our careful washout technique did not impair the EDHF-mediated endothelial function and that the substance P–induced relaxation was reproducible in the same coronary preparation.
Exposure to hyperkalemia.
In separate experiments, rings were exposed to hyperkalemic solutions that contained a 20 mmol/L concentration of K in the Krebs solution. After exposure for 1 hour, the chamber solutions were changed to normal Krebs solution again and the rings were frequently washed with Krebs solution to restore the baseline conditions. The previously described protocols 1, 2, and 4 were repeated before the concentration-relaxation curves to substance P were established.
Other arteries were incubated with a 50 mmol/L concentration of K in the Krebs solution. After the incubation, protocols 1 and 4 were studied in those arteries.
Indomethacin, L-NNA, tetraethylammonium, and glibenclamide were added 30 minutes before the concentration-relaxation curves for substance P were started. Only one concentration-relaxation curve was obtained for each coronary ring. For 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% O2/5% CO2 at 37° C to exclude the effect of ischemia and temperature.
Electrophysiologic studies (membrane potential measurement).
Porcine coronary rings were cut along the longitudinal axis and mounted on the bottom of a 2.5 ml organ bath with the intimal side upward. After 60 minutes of equilibrium, a glass microelectrode filled with a 3 mol/L concentration of KCl (tip resistance 40 to 80 MW) was inserted into a smooth muscle cell from the endothelial side. 8,12,14 The electrical signals were amplified by means of a microelectrode amplifier (Axoprobe-1A, H.V. electrometer model 400B, Axon Instruments, Inc., Foster City, Calif.). The membrane potential was displayed continuously on an oscilloscope (COS5020-ST, Gould, Cleveland, Ohio) and simultaneously recorded on a tape recorder (PCM-2 analog/digital video cassette recorder, Medical System Corp., Greenvale, N.Y.). The criteria of impaling cells are a sudden negative change in voltage followed by a stable negative voltage for more than 1 minute and an instantaneous return to the previous voltage level on dislodgment of the microelectrode. 9,11
Experimental protocol.
After stabilization for 60 minutes, concentration-response curves were established for substance P (-11 to -8 log M) in the presence of indomethacin (7 µmol/L) and L-NNA (300 µmol/L) for 30 minutes as the control. Pilot experiments (n = 7) demonstrated that the concentration-response curves, after careful wash out (by slowly changing the bath solution), could be repeated without significant changes. These pilot experiments also ruled out the possibility that any changes in membrane potential after exposure to K were caused by mechanical injury because of our wash-out technique. The vessel was repeatedly washed to restore the resting membrane potential. The artery was then exposed to the hyperkalemic solution (Krebs solution with a K concentration of 20 mmol/L, which replaced the Na+) for 1 hour. During the incubation, the artery was continuously perfused at a rate of 3 ml/min and was oxygenated with a mixture of 95% O2/5% CO2 to exclude the effect of ischemia. The artery was repeatedly washed with the normal Krebs solution for 30 minutes. After the washout, indomethacin (7 µmol/L) and L-NNA (300 µmol/L) were added to incubate the ring for another 30 minutes and the concentration-response curve was established for substance P (-11 to -8 log M).
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 = MAp/(Ap + Kp), 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 this fitted equation, the mean EC50 value plus or minus the standard error of the mean was calculated for each group.
Statistical analysis.
Data were analyzed by analysis of variance (followed by Scheffe's test), unpaired, or paired t test when appropriate. A value of p < 0.05 was considered significant.
Drugs.
Drugs used and their sources were as follows: substance P, L-NNA, indomethacin, glibenclamide, and tetraethylammonium (Sigma, 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. Glibenclamide was dissolved in 95% ethanol to a concentration of 1 mmol/L. In control experiments, ethanol did not show any effects on the substance P–induced relaxation at the concentration of 0.3%, as has also been observed by others. 3,5
Results
Isometric tension measurement.
The diameter of the vascular rings at a pressure of 100 mm Hg was 3.3 ± 0.2 mm and the transmural pressure was 70.8 ± 2.8 mm Hg at 90% of the diameter at 100 mm Hg. 16,17
Basal tone.
The change in the basal tone induced by various inhibitors was minimum. In all groups, indomethacin plus glibenclamide 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 gm. In the rings treated with a 20 mmol/L concentration of K, the change of the tone was also 0.2 ± 0.1 gm. In the rings treated with a 50 mmol/L concentration of K, the change of the tone was 0.8 ± 0.1 gm. However, tetraethylammonium significantly increased the resting tone. In the control group, the resting tone increased by 4.1 ± 0.6 gm (p < 0.05) whereas in treatment with a 20 mmol/L concentration of K, it was 4.3 ± 0.8 gm (p < 0.05).
Comparison of precontraction.
Precontraction by U46619 was affected by the inhibitors. Table I gives details of the precontraction force. In the control group, after treatment with indomethacin and L-NNA (n = 6), the tone was 11.1 ± 1.0 gm, whereas it was 3.3 ± 0.6 gm after treatment with indomethacin and glibenclamide (n = 5, p = 0.0002). Further addition of tetraethylammonium to indomethacin and L-NNA also slightly reduced the contraction by U46619 (7.9 ± 0.9 gm, p = 0.09). Similar results were also seen in other groups (Table I). In the group treated with a 20 mmol/L concentration of K, the decrease of precontraction by indomethacin, L-NNA, and tetraethylammonium reached statistical significance (5.8 ± 0.5 gm vs 11.4 ± 1.0 gm, p < 0.01).
|
|
(Table II).
|
|
|
In endothelium-denuded rings, substance P did not induce any relaxation and this confirms that the relaxations observed in the present study were endothelium-dependent (Figs. 2 through 4).
Membrane potential measurement.
The resting membrane potential was -59.3 ± 1.1 mV (n = 6).
Substance P–induced hyperpolarization.
Substance P induced concentration-dependent hyperpolarization in the coronary artery at the concentration of -11 to -8 log M. The maximal hyperpolarization was -91.3 ± 5.3 mV (n = 6). After incubation with K (20 mmol/L) for 1 hour, the vessels were depolarized to -30.8 ± 1.8 mV (p < 0.0001). The arteries were repeatedly washed for 30 minutes and incubated with the inhibitors for another 30 minutes (total 1 hour) and the membrane potential still remained higher than the control (-56.8 ± 1.1 mV, n = 6, p < 0.05). At the concentrations of -11 to -8 log M, the substance P–induced hyperpolarization was significantly inhibited by the previous hyperkalemic incubation (Figs. 5 and 6). The difference was most significant at -8 log M (-67 ± 3.6 vs -91.3 ± 5.3 mV, p = 0.003).
|
|
This study has demonstrated (1) that indomethacin- and L-NNA–resistant endothelium-dependent (EDHF related) relaxation and the associated membrane hyperpolarization in the coronary artery are reduced by exposure to hyperkalemia; (2) that this effect is vasoconstrictor independent; and (3) that the mechanism of this reduction of relaxation and hyperpolarization is related to the inhibition of KCa channels and prolonged depolarization in the coronary smooth muscle cells. These findings are illustrated in Fig. 1. The findings from the present study, in addition to previous findings, may reveal a new mechanism for endothelial dysfunction after exposure to hyperkalemic cardioplegic or organ-preservation solutions and may therefore have strong clinical implications.
Exposure to hyperkalemia and EDHF-related relaxation.
In our studies, two other major components of endothelium-dependent relaxation, the cyclooxygenase and EDNO pathways, were blocked by indomethacin and L-NNA and, therefore, the residual relaxation was obviously through the noncyclooxygenase and non-EDNO mechanism, that is, it was related to the effect of EDHF. In the porcine coronary artery, EDHF plays a role in endothelium-dependent relaxation and this was partially reflected in our previous study when the arteries were precontracted by the depolarizing agent K. 6 This is even more significant when the coronary artery is precontracted with a receptor stimulant, U46619, as shown in the present study. When inhibitors for both cyclooxygenase and EDNO pathways were present, the residual relaxation was still 93% of the precontraction. This suggests the role of EDHF in regulating the coronary tone at least under the stimulated condition.
In the present study, we used U46619, a thromboxane A2 mimetic vasoconstrictor, to precontract the coronary arteries to exclude the depolarizing effect of the vasoconstrictor used for precontraction. In our previous study, 6 after exposure of vessels to hyperkalemia, precontraction was induced by the depolarizing agent K. However, when vessels are contracted by K, EDHF-mediated hyperpolarization may be partially blocked by the K-induced depolarization. As shown in our studies, EDHF-mediated relaxation in receptor-mediated precontraction (by U46619) was 93% in the present study, compared with only 39.7% in the K-induced precontraction. 6 Our present study demonstrates that the reducing effect of hyperkalemia on EDHF-related, endothelium-dependent relaxation also exists in receptor-mediated precontraction. This is shown by the observations that when cyclooxygenase and nitric oxide pathways were inhibited by indomethacin and L-NNA, the residual relaxation (93%) was reduced by the exposure to hyperkalemia to 48% (by K concentration of 20 mmol/L) or 30% (by K concentration of 50 mmol/L). Taken together with the results from the previous study, our data suggest that the reduction of the residual relaxation by hyperkalemia is not vasoconstrictor dependent. Therefore this effect is a uniform phenomenon affecting the coronary endothelium–smooth muscle interaction under various situations.
Exposure to hyperkalemia and membrane hyperpolarization (electrophysiologic study).
To further study whether the foregoing observations regarding relaxation were related to the effect of EDHF, in the present study we directly measured the membrane potential of the coronary smooth muscle. This was designed in view of the previous observation that EDHF-related endothelium-dependent relaxation is coupled with the membrane hyperpolarization that is the reason for the use of the term EDHF. If the reduced relaxation is truly related to the effect of EDHF, the membrane potential must also be affected. The present study demonstrated a few interesting results in terms of the membrane potential. First, with the presence of specific inhibitors for both cyclooxygenase (indomethacin) and EDNO (L-NNA), the substance P–induced, endothelium-dependent relaxation was associated with hyperpolarization of the membrane potential of the coronary artery smooth muscle. This result clearly demonstrates that the indomethacin- and L-NNA–resistant endothelium-dependent relaxation in the porcine coronary artery is mediated by EDHF. Second, the membrane depolarization induced by exposure to hyperkalemia was prolonged (-56.8 ± 1.1 vs -59.3 ± 1.1 mV, Figs. 5 and 6) even after repeated washing for 30 minutes plus incubation with inhibitors for another 30 minutes. This prolonged, partial depolarization obviously contributes to the reduced hyperpolarization and relaxation in response to substance P. With the resting membrane potential higher than the usual value (partial depolarization), membrane hyperpolarization is more difficult.
However, the partial depolarization cannot be the only mechanism of the reduced EDHF-related relaxation and hyperpolarization. This is because the reduction of the substance P–stimulated hyperpolarization in the arteries that had been exposed to hyperkalemia reached a greater extent (-67 ± 3.6 vs -91.3 ± 5.3 mV, p = 0.003, Figs. 5 and 6) compared with the small changes in the resting membrane potential (-56.8 ± 1.1 vs -59.3 ± 1.1 mV). Obviously, other mechanisms are involved in such a great reduction of the membrane potential.
K channels and the effect of hyperkalemia.
K channels are usually subdivided according to their mode of activation. 19 The involvement of the subtype of K channels is probably species and agonist dependent. 8 Probably the relative importance of the three EDRFs in regulating vascular tone is also species dependent. Although KATP channels have been suggested to be involved in the hyperpolarization of smooth muscle by EDHF, 12-14 the KCa channels are likely to be involved in hyperpolarization in the coronary artery. 15 In the porcine coronary artery, EDHF is related to glibenclamide-insensitive K channels. 20 To examine the role of the KCa channels, we studied inhibitory effects of tetraethylammonium in the present study. Tetraethylammonium is generally considered a specific KCa blocker at the concentration of less than 1 mmol/L, 21 although it may be less specific for K channels at higher concentrations. The KATP blocker glibenclamide was also applied to examine the role of KATP channels.
Our experiments, by using tetraethylammonium and glibenclamide, demonstrated that in the porcine coronary artery EDHF-related relaxation mainly involves KCa channels, although the KATP channel may also be involved to a lesser extent. This is demonstrated by the results that tetraethylammonium, but not glibenclamide, could greatly inhibit the residual relaxation resistant to indomethacin and L-NNA (from 93% to 33%). In fact, glibenclamide only slightly reduced the relaxation (to 71.5%, Fig. 2). Therefore the present study demonstrates that in the porcine coronary artery the major component of substance P–induced, indomethacin- and L-NNA–resistant (EDHF related) relaxation is related to the opening of the KCa channels.
In summary, our experiments suggest that the reduced residual relaxation described herein is coupling with the reduced hyperpolarization, that is, it is coupling with a reduced effect of EDHF. This may imply that exposure to hyperkalemia may directly affect the response of smooth muscle to EDHF, possibly through inhibiting the KCa channels. KATP channels may also be involved. In addition, partial membrane depolarization may play a role.
We previously illustrated the possible mechanism of hyperkalemia on endothelial function. 6 The findings from the present study enable us to give more detailed suggestions on the mechanism. As shown in Fig. 1, although hyperkalemia does not directly affect the EDNO and prostaglandin I2 pathways, it reduces the EDHF-related relaxation by two means. First, it inhibits K channels, particularly KCa channels, similar to the effect of tetraethylammonium. To a lesser extent, it also affects KATP channels. Second, it has a prolonged depolarizing effect on the membrane. These actions greatly affect the hyperpolarizing effect of EDHF and therefore reduce EDHF-related relaxation and the associated membrane hyperpolarization.
Clinical implications.
As suggested before, if both EDNO and EDHF are active in regulating the tone of the coronary circulation, then the present study supports the proposed new mechanism for coronary dysfunction after exposure to hyperkalemia. 6 When EDHF-mediated relaxation is reduced, the artery must have a higher tendency to contract and this may lead to coronary spasm that could be critical in myocardial perfusion, particularly combined with the impaired production of EDNO after ischemia. 22 During cardiac operations, the heart is arrested by perfusion of hyperkalemic cardioplegic solutions through the coronary circulation. Such exposure may reduce the vasorelaxant effect of EDHF during the reperfusion period even after washout of the hyperkalemic solution for 1 hour, as demonstrated in the present study.
In addition, hyperkalemic solutions such as the University of Wisconsin solution (with a potassium concentration as high as 125 mmol/L) and Euro-Collins solution (with a potassium concentration of 115 mmol/L) have been widely used to preserve organs (heart, lung, and others). 23-26 Therefore our findings also have implications in organ transplantations. In addition, because endothelium plays an important role in antiplatelet aggregation and prevention of atherosclerosis, the endothelial dysfunction found in the present study may have an adverse effect on the long-term results of heart or other organ transplantation, although it is still unclear what the correlation is between the EDHF-mediated endothelial function and the development of arteriosclerosis. In fact, it has been reported that in cardiac allografts preserved in University of Wisconsin solution, the incidence of late graft atherosclerosis was twice as high as that in grafts preserved in Stanford solution. 27 The findings from the present study may explain, at least as one of the causes, the higher atherosclerotic incidence after heart transplantation with the use of University of Wisconsin solution. However, further studies are required to clarify the importance of the present findings in the maintenance of coronary circulation and the development of posttransplantation atherosclerosis.
On the other hand, the experimental environment may not be exactly the same as in various clinical settings and therefore the application of our findings in clinical situations must be cautious. Furthermore, our study was conducted in the large coronary artery and we understand that there may be difference between the large and resistance coronary arteries with regard to the effect of hyperkalemia. This issue will be addressed in our future studies.
We conclude that depolarizing arrest (exposure to hyperkalemia) reduces EDHF-mediated relaxation and associated membrane hyperpolarization in the porcine coronary artery and that this effect is vasoconstrictor independent. The mechanism of this reduction is related to the inhibition of KCa channels, although the KATP channels may also be involved to a lesser extent, and to prolonged partial membrane depolarization. These findings, in addition to the previous findings, provide useful information for understanding coronary dysfunction after exposure to depolarizing (hyperkalemic) solutions and therefore have strong clinical implications. Future development of cardioplegic or organ-preservation solutions should restore the EDHF-related relaxation and hyperpolarization to obtain the "perfect" protection.
Acknowledgments
We sincerely thank Dr. T. M. Wong and Dr. J. Z. Sheng at the Department of Physiology, The University of Hong Kong, for the kind assistance in the experiments measuring the membrane potential.
References
This article has been cited by other articles:
|
|
 |
|
  Y.-Y. Dong, M. Wu, A. P.C. Yim, and G.-W. He Effect of hypoxia-reoxygenation on endothelial function in porcine cardiac microveins. Ann. Thorac. Surg., May 1, 2006; 81(5): 1708 - 1714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Dong, M. Wu, A. P.C. Yim, and G.-W. He Hypoxia-Reoxygenation, St. Thomas Cardioplegic Solution, and Nicorandil on Endothelium-derived Hyperpolarizing Factor in Coronary Microarteries Ann. Thorac. Surg., November 1, 2005; 80(5): 1803 - 1811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang and G.-W. He Effect of Cardioplegic and Organ Preservation Solutions and Their Components on Coronary Endothelium-Derived Relaxing Factors Ann. Thorac. Surg., August 1, 2005; 80(2): 757 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, R.-Z. Zhang, A. P.C. Yim, and G.-W. He Release of Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor (EDHF) in Porcine Coronary Arteries Exposed to Hyperkalemia: Effect of Nicorandil Ann. Thorac. Surg., June 1, 2005; 79(6): 2065 - 2071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zou, Q. Yang, A. P. C. Yim, and G.-W. He Impaired endothelium-derived hyperpolarizing factor-mediated relaxation in porcine pulmonary microarteries after cold storage with Euro-Collins and University of Wisconsin solutions J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 208 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, Y.-C. Liu, W. Zou, A. P. C. Yim, and G.-W. He Protective effect of magnesium on the endothelial function mediated by endothelium-derived hyperpolarizing factor in coronary arteries during cardioplegic arrest in a porcine model J. Thorac. Cardiovasc. Surg., August 1, 2002; 124(2): 361 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Ren, Q. Yang, H. Storm Floten, and G.-W. He Hypoxic preconditioning in coronary microarteries: role of EDHF and K+ channel openers Ann. Thorac. Surg., July 1, 2002; 74(1): 143 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Parolari, P. Rubini, A. Cannata, L. Bonati, F. Alamanni, E. Tremoli, and P. Biglioli Endothelial damage during myocardial preservation and storage Ann. Thorac. Surg., February 1, 2002; 73(2): 682 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zou, Q. Yang, A. P.C. Yim, and G.-W. He Epoxyeicosatrienoic acids (EET11,12) may partially restore endothelium-derived hyperpolarizing factor-mediated function in coronary microarteries Ann. Thorac. Surg., December 1, 2001; 72(6): 1970 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Krassoi, J. Pataricza, L. L. Torday, A. Kun, and J. Gy. Papp Improvement by phosphoramidon of damaged endothelial function in porcine coronary artery Ann. Thorac. Surg., September 1, 2000; 70(3): 878 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-W. He Invited Commentary Ann. Thorac. Surg., September 1, 2000; 70(3): 882 - 882. [Full Text] [PDF]
|
|
|
|
|
|
Z.-D. Ge and G.-W. He ALTERED ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR-MEDIATEDENDOTHELIAL FUNCTION IN CORONARY MICROARTERIES BY ST THOMAS' HOSPITAL SOLUTION J. Thorac. Cardiovasc. Surg., July 1, 1999; 118(1): 173 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-W. He Potassium-channel opener in cardioplegia may restore coronary endothelial function Ann. Thorac. Surg., October 1, 1998; 66(4): 1318 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-W. He and C.-Q. Yang Impaired Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation In Coronary Arteries By Cold Storage With University Of Wisconsin Solution J. Thorac. Cardiovasc. Surg., July 1, 1998; 116(1): 122 - 130. [Abstract] [Full Text]
|
|
|
|
|
|
G.-W. He Verapamil plus nitroglycerin solution maximally preserves endothelial function of the radial artery: Comparison with papaverine solution J. Thorac. Cardiovasc. Surg., June 1, 1998; 115(6): 1321 - 1325. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
