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EDITORIAL |
Hong Kong, China
Vascular endothelium has multiple functions including regulating vascular tone, preventing platelet aggregation, anti-proliferation etc. All these functions are important in physiological and pathophysiological status. The regulation of vascular tone – the endothelium-dependent relaxation is mediated by three endothelium-derived relaxing factors1 (EDRFs) – nitric oxide (NO), prostacyclin (PGI2), and an unidentified endothelium-derived hyperpolarizing factor (EDHF).
PGI2 is the first defined relaxing factor derived from endothelium and it is converted from arachidonic acid (AA) by cyclooxygenase (COX). PGI2 causes vasorelaxation in most arteries, including the coronary bed by increase of cyclic 3', 5'-adenosine monophosphate (cAMP). Different types of potassium (K+) channels are also involved.
NO is synthesized from the amino acid L-arginine by NO synthase (NOS). There are at least two major NOS isoforms: 1) cNOS is expressed constitutively in neurons and vasculature that is involved in cell communication and is activated by an increase in intracellular calcium. 2) iNOS exists in macrophages to participate in host defense and is not normally found in endothelial cells or vascular smooth muscle unless induced by cytokines. NO induces vasorelaxation through cyclic 3', 5'-guanosine monophosphate (cGMP) mechanism.2 Several types of K+ channels are also involved in NO-mediated hyperpolarization.
The endothelium-dependent hyperpolarization and relaxation are only partially inhibited or not changed with the presence of COX and NOS inhibitors, indicating the existence of a novel vasorelaxant agent named EDHF, which is distinct from PGI2 and NO.3,4 Several substances have been suggested to be EDHF, such as epoxyeicosatrienoic acid (EETs), anadamide, K+ , H2O2, citrulline, NH3 and ATP.3 It has also been suggested that the so-called EDHF is merely an electrical signal conducted from the endothelial cell to the underlying smooth muscle cell through myoendothelial gap junctions, the intercellular connection between the layer of endothelium and smooth muscle.5 EDHF hyperpolarizes and relaxes blood vessels through opening of certain K+ channels, particularly calcium-activated potassium channels on the smooth muscle cell.
The above endothelial functions are all related to cardiac surgery. For example, the function of preventing platelet aggregation is directly related to the inflammatory process during and after cardiopulmonary bypass. Again, the anti-proliferation effect of the endothelium is related to the long-term patency of the coronary artery bypass grafts and the atherosclerotic disease after heart transplantation. However, probably the most immediate effect of endothelial dysfunction is seen under the following two circumstances – coronary endothelial function after cardiac arrest for open heart surgery (or donor heart preserved with organ preservation solutions) and the endothelial function in the coronary artery bypass grafts.
CORONARY ENDOTHELIAL FUNCTION IN CARDIAC SURGERY
During open heart surgery, cardioplegia is usually used to initially stop and then maintain the still condition of the heart. The injury to the heart involves 1) the ischemia-reperfusion injury to the myocytes and coronary circulation and 2) possible injury to the coronary circulation by the cardioplegia due to its hyperkalemic components. The injury to the coronary circulation may involve both NO and EDHF mechanisms that are thought to be the two major mechanisms in the endothelium-smooth muscle interaction that is particularly important in maintaining adequate vascular tone. The NO mechanism is susceptible to ischemia-reperfusion whereas the EDHF mechanism may be altered by the hyperkalemic cardioplegia. To further protect the heart, supplemental therapy for NO and optimizing the components of cardioplegia to restore the EDHF-mechanism may be important.
In addition to usual cardioplegic solutions, for organ transplantation, cardioplegia or organ preservation solutions are used to preserve the heart or other organs. The endothelium-smooth muscle interaction may also be changed due to a similar reason, as mentioned above. Therefore, protection of the endothelium-smooth muscle interaction should include these two important functions.
NO-RELATED FUNCTION IN CARDIAC SURGERY
The dysfunction of the NO mechanism is mainly due to ischemia-reperfusion injury but not to the effect of cardioplegia. In most of the previous studies, the effect of ischemia-reperfusion and the effect of cardioplegia are combined and the measurement is often the coronary flow in the perfused heart and the so-called effect of cardioplegia is often combined with the effect of ischemia-reperfusion as aforementioned. There is little direct evidence showing that the reduced production of NO during cardiac surgery is due to exposure to the components of cardioplegia, per se, without ischemia-reperfusion. Studies from other and our laboratories, in contrast, have shown that crystalloid hyperkalemic cardioplegia does not significantly affect the NO-related, endothelium-dependent relaxation for up to 4 hours. We have good reasons, therefore, to believe that widely used hyperkalemic cardioplegia has little effect on the NO-related function during the usual cardiac arrest time (1–2 hours). The major cause of injury to the NO-related function is due to the ischemia-reperfusion injury to the coronary endothelial function but not due to the cardioplegia itself, per se. Addition of L-arginine, the precursor of NO, or NO donors, such as nitrovasodilators, has been demonstrated to be able to recover the NO function.
Preconditioning (transient ischemia) has been shown to prevent the impairment of ischemia-reperfusion that is related to the protection of NO mechanism. This method provides a new approach to the protection of the NO function in cardiac surgery. However, further studies on the mechanism and methods are required.
EDHF-RELATED ENDOTHELIAL FUNCTION IN CARDIAC SURGERY
The other major EDRF – EDHF is, in contrast to the NO function, susceptible to cardioplegia although there is also a report demonstrating that this function may be impaired by hypoxia. We have conducted a series of experiments to investigate the endothelium-smooth muscle interaction in the coronary circulation regarding exposure to cardioplegia and organ preservation solution at two levels – the large conductance coronary arteries and micro-coronary arteries by using multiple methods. The studies demonstrated that 1) the EDHF-mediated endothelial function is impaired by incubation with hyperkalemic (K+ 20–125 mmol including University of Wisconsin) solutions; 2) The mechanism involves prolonged depolarization; 3) magnesium has a protective effect; and 4) hyperpolarizing cardioplegia, using K+ channel openers (KCOs) for cardioplegia, preserves coronary endothelial function.
To restore the EDHF-mediated endothelial function, several methods such as EDHF analogues, EETs and K+ channel openers and preconditioning are proposed to use in cardiac surgery but this needs to be further studied.
ENDOTHELIAL FUNCTION IN THE CORONARY ARTERY BYPASS GRAFTS
Endothelium also plays an important role in the grafts used in coronary artery bypass grafting (CABG) regarding vasospasm and long-term patency. Generally, arteries have more significant endothelium-dependent relaxation than the veins. Recently, by using direct measurement of NO and cellular membrane potential of the smooth muscle in the grafts, we have clearly shown that the endothelial cell of the arterial graft, the internal mammary artery (IMA), releases more NO and EDHF than the saphenous vein. This may be the major reason for the superior patency of the arterial grafts.6
Compared to the marked difference regarding the NO and EDHF release between the IMA and saphenous vein, the difference among arteries may be less significant. However, our recent studies demonstrate that there are differences even among arteries used for CABG. For example, the endothelium of the IMA releases more NO and EDHF than the radial artery.7
In summary, endothelial function becomes a major theme in cardiac surgery because of the importance of endothelium in maintaining the vascular tone and other functions. It is particularly important to understand that coronary endothelial dysfunction may be one of the major causes of low perfusion of the myocardium after cardiac arrest. Further, endothelium plays a major role in the maintenance of the vascular tone and long-term patency of the CABG grafts. It is therefore important to further investigate the methods to protect the endothelial function in cardiac surgery.
ACKNOWLEDGMENTS
The work described in this paper was fully supported by grants from the Research Grants Council of the Hong Kong, China (Project No. CUHK4127/01M and CUHK4383/03M) and the Providence St. Vincent Medical Foundation, Oregon, USA.
REFERENCES
This article has been cited by other articles:
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  S.-A. Hassantash, B. Bikdeli, S. Kalantarian, M. Sadeghian, and H. Afshar Pathophysiology of Aortocoronary Saphenous Vein Bypass Graft Disease Asian Cardiovasc Thorac Ann, August 1, 2008; 16(4): 331 - 336. [Abstract] [Full Text] [PDF]
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