Effect of Cardioplegic and Organ Preservation Solutions and Their Components on Coronary Endothelium-Derived Relaxing Factors
2005; Elsevier BV; Volume: 80; Issue: 2 Linguagem: Inglês
10.1016/j.athoracsur.2004.10.003
ISSN1552-6259
Autores Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoCardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) during cardiac operation (and heart transplantation). Because of differences between cardiac myocytes and vascular (endothelial and smooth muscle) cells in structure and function, the solutions may have an adverse effect on coronary vascular cells. However, such effect is often complicated by many other factors such as ischemia-reperfusion injury, temperature, and perfusion pressure or duration. To evaluate the effect of a solution on the coronary endothelial function, a number of points should be taken into consideration. First, the overall effect on endothelium should be identified. Second, the effect of the solution on the individual endothelium-derived relaxing factors (nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor) must be distinguished. Third, the effect of each major component of the solution should be investigated. Lastly, the effect of a variety of new additives in the solution may be studied. Based on available literature these issues are reviewed to provide information for further development of cardioplegic or organ preservation solutions. Cardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) during cardiac operation (and heart transplantation). Because of differences between cardiac myocytes and vascular (endothelial and smooth muscle) cells in structure and function, the solutions may have an adverse effect on coronary vascular cells. However, such effect is often complicated by many other factors such as ischemia-reperfusion injury, temperature, and perfusion pressure or duration. To evaluate the effect of a solution on the coronary endothelial function, a number of points should be taken into consideration. First, the overall effect on endothelium should be identified. Second, the effect of the solution on the individual endothelium-derived relaxing factors (nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor) must be distinguished. Third, the effect of each major component of the solution should be investigated. Lastly, the effect of a variety of new additives in the solution may be studied. Based on available literature these issues are reviewed to provide information for further development of cardioplegic or organ preservation solutions. Ischemia-reperfusion injury is the major problem in open-heart operations, including heart transplantation. The goal of cardioplegia was to eliminate this injury. Cardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) from ischemia-reperfusion injury. Subsequently, researchers found that, despite their protective effect on cardiac myocytes, these solutions may impair coronary vascular endothelial cells. These opposite effects are due to the differences in structure and function between cardiac myocytes and coronary vascular (endothelial and smooth muscle) cells. A number of issues should be taken into account in the investigations regarding the effect of cardioplegic/organ preservation solutions on the coronary endothelial function. First, in the whole heart, the overall effect of these solutions is a result of the combination of the effect on the cardiac myocytes and the effect on the coronary endothelium. Second, even in studies focused on endothelial function, the effect of the solutions has often been mixed with ischemia-reperfusion injury and other factors. The goal of this review is to discuss the effect of the solutions and their components on the endothelium to provide information for further development of protective solutions. In addition, this review emphasizes the effect of cardioplegic/organ preservation solutions on individual endothelial factors. A comprehensive English literature search through PubMed was performed with closing date of June 28, 2004. Multiple keywords were used for searching as follows: [(endothelium OR endothelial function OR EDRF)] AND [(cardiac operation OR heart transplantation)] OR [(cardioplegia OR cardioplegic solution OR organ preservation solution OR hyperkalemia)] AND [(cardioplegic additives OR supplementation OR adjunct)]. The focus of the literature selection was original studies. Book chapters or references before 1970 were occasionally cited for historic or technical aspects. The introduction of cardioplegia for myocardial protection was a breakthrough in cardiac operations. Melrose and colleagues [1Melrose D.G. Dreyer B. Bentall H.H. Barker J.B. Elective cardiac arrest.Lancet. 1955; 2: 21-22Abstract Google Scholar] in 1955 proposed the concept of chemical heart arrest with the mixture of blood and 2.5% solution of potassium citrate with the concentrations of potassium varying from 9 to 245 mEq/L in experimental studies, and the method was soon used clinically by Effler in 1957 [2Effler D.B. Knight H.F. Groves L.K. Kolff W.J. Elective cardiac arrest for open heart surgery.Surg Gynecol Obstet. 1957; 105: 407-416Google Scholar]. However, the extremely high potassium concentrations in the Melrose solution were later demonstrated to induce myocardial necrosis and then abandoned. Bretschneider [3Bretschneider H.J. Hubner G. Knoll D. Lohr B. Nordbeck H. Spieckermann P.G. Myocardial resistance and tolerance to ischemia physiological and biochemical basis.J Thorac Cardiovasc Surg. 1975; 16: 241-260Google Scholar] reported to use low-sodium, mildly hyperkalemic (7 mEq/L), calcium-free procaine solution in Germany 1975, and Gay and Ebert [4Gay W.A. Ebert P.A. Functional, metabolic, and morphologic effects of potassium-induced cardioplegia.Surgery. 1973; 74: 284-290PubMed Google Scholar] found that potassium crystalloid cardioplegia at a potassium concentration of 24 mEq/L increased recovery after ischemia. The effectiveness of moderately hyperkalemic potassium cardioplegia was then supported and was widely demonstrated by excellent clinical results in the 1970s. One of the widely used cardioplegic solutions was St. Thomas Hospital (ST) solution [5Hearse D.J. Stewart D.A. Braimbridge M.V. Cellular protection during myocardial ischemia the development and characterization of a procedure for the induction of reversible ischemic arrest.Circulation. 1976; 54: 193-202Crossref PubMed Google Scholar]. During the 1980s and early 1990s, hundred of studies of cardioplegia were published. Due to its superb operating conditions and its effectiveness in myocardial preservation, cold cardioplegic arrest became the most commonly used method until blood cardioplegia became popular. During this period, a number of crystalloid cardioplegic solutions were developed, including histidine-tryptophan-ketoglutarate (HTK) solution [6Gebhard M.M. Preusse C.J. Schnabel P.A. Bretschneider H.J. Different effects of cardioplegic solution HTK during single or intermittent administration.Thorac Cardiovasc Surg. 1984; 32: 271-276Crossref PubMed Google Scholar]. Although the composition varies in different solutions, the pharmacologic principles involved in myocardial protection are similar [7Vinten-Johansen J. Hammon J.W. Myocardial protection during cardiac surgery.in: Gravlee G.P. Davis R.F. Utley J.R. Cardiopulmonary Bypass Principles and Practice. Williams & Wilkins, Baltimore, MD1993: 155-206Google Scholar, 8Allen B.S. Buckberg G.D. Myocardial management in arterial revascularization.in: He G.-W. Arterial Grafts for Coronary Artery Bypass Surgery. Springer, Singapore1999: 83-105Google Scholar]. First, immediate arrest induced by K+, Mg2+, procaine, profound hypocalcemia, or a combination of these modalities lowers energy demand to avoid depletion of the high-energy phosphate pool and conserves the myocardial energy reserves that can be used during the period of ischemia to maintain ionic and metabolic homeostasis and, consequently, leads to the better tolerance to ischemia. Second, reduction of myocardial temperature during arrest or storage lowers metabolic rate during ischemia. Third, supplementation of glucose and amino acid (ie, glutamate or aspartate) enhances anaerobic or aerobic energy production (or both) with a buffer such as tris (hydroxymethyl) aminoethane, bicarbonate, phosphate, and histidine and optimizes the small energy output of anaerobic glycolysis during ischemia. Fourth, membrane stabilization provided by exogenous additives (ie, steroids, procaine, oxygen radical scavengers, Ca2+ antagonists), hypocalcemia, or enrichment of Mg2+ may counteract the myocardial injury during ischemia and reperfusion. Lastly, addition of an osmotic agent such as mannitol and adjustment of infusion pressure limit myocardial edema and prevent the occurrence of "no-flow phenomenon" [7Vinten-Johansen J. Hammon J.W. Myocardial protection during cardiac surgery.in: Gravlee G.P. Davis R.F. Utley J.R. Cardiopulmonary Bypass Principles and Practice. Williams & Wilkins, Baltimore, MD1993: 155-206Google Scholar, 8Allen B.S. Buckberg G.D. Myocardial management in arterial revascularization.in: He G.-W. Arterial Grafts for Coronary Artery Bypass Surgery. Springer, Singapore1999: 83-105Google Scholar]. Cold oxygenated blood with potassium as the arresting agent was described in the 1970s [9Follette D.M. Mulder D.G. Maloney J.V. Buckberg G.D. Advantages of blood cardioplegia over continuous coronary perfusion or intermittent ischemia experimental and clinical study.J Thorac Cardiovas Surg. 1978; 76: 604-619Google Scholar, 10Laks H. Barner H.B. Kaiser G. Cold blood cardioplegia.J Thorac Cardiovasc Surg. 1979; 77: 319-322PubMed Google Scholar, 11Barner H.B. Blood cardioplegia a review and comparison with crystalloid cardioplegia.Ann Thorac Surg. 1991; 52: 1354-1367Abstract Full Text PDF PubMed Google Scholar]. The presence of red cells and plasma proteins as well as other blood components provides a strong capacity for oxygen carrying, buffering, and antioxidation [11Barner H.B. Blood cardioplegia a review and comparison with crystalloid cardioplegia.Ann Thorac Surg. 1991; 52: 1354-1367Abstract Full Text PDF PubMed Google Scholar]. The most commonly used method is mixing the crystalloid cardioplegia with blood in a ratio of 1:4 [8Allen B.S. Buckberg G.D. Myocardial management in arterial revascularization.in: He G.-W. Arterial Grafts for Coronary Artery Bypass Surgery. Springer, Singapore1999: 83-105Google Scholar, 11Barner H.B. Blood cardioplegia a review and comparison with crystalloid cardioplegia.Ann Thorac Surg. 1991; 52: 1354-1367Abstract Full Text PDF PubMed Google Scholar]. The final delivery concentrations of potassium remain at 20 to 25 mEq/L for the initial prompt arrest of the heart and 8 to 10 mEq/L for the subsequent delivery of the solution [8Allen B.S. Buckberg G.D. Myocardial management in arterial revascularization.in: He G.-W. Arterial Grafts for Coronary Artery Bypass Surgery. Springer, Singapore1999: 83-105Google Scholar]. The final concentration of Mg2+ and procaine is less than that in crystalloid cardioplegic solutions such as ST. For example, the concentration of Mg2+ is 5 to 6 mEq/L in cold blood cardioplegia and 10 to 12 mEq/L in warm blood cardioplegia in the Buckberg blood cardioplegic solution [8Allen B.S. Buckberg G.D. Myocardial management in arterial revascularization.in: He G.-W. Arterial Grafts for Coronary Artery Bypass Surgery. Springer, Singapore1999: 83-105Google Scholar]. Since the 1980s, blood cardioplegia has become the choice of myocardial protection in most cardiac units, although crystalloid cardioplegia is still used today because of either the preference of the surgeon or economic concerns. Preservation of the heart with organ preservation solutions has been demonstrated as a useful strategy in heart transplantation. These solutions protect the heart by controlling the risk factors involved in ischemic-reperfusion injury with similar principles of cardioplegic solutions, including reduction of oxygen demand, cellular swelling, extracellular edema, and Ca2+ overload [12Jahania M.S. Sanchez J.A. Narayan P. Lasley R.D. Mentzer Jr, R.M. Heart preservation for transplantation principles and strategies.Ann Thorac Surg. 1999; 68: 1983-1987Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. In fact, commonly in cardiac operations one solution serves as both a cardioplegic and heart preservation solution. The composition of various crystalloid cardioplegic or heart preservation solutions are listed in Table 1.Table 1Composition of Krebs, UW, ST, HTK, and Celsior SolutionsCompositionKrebsUWSTHTKCelsiorNa+ (mmol/L)143.42913815100K+ (mmol/L)5.9125201015Ca2+ (mmol/L)2.5—2.70.0150.26Mg2+ (mmol/L)1.2516413Cl− (mmol/L)128.7—15746.01541.5HCO3− (mmol/L)25—8—SO42− (mmol/L)1.25——0H2PO4− (mmol/L)1.225——0HPO42− (mmol/L)————Procaine (mmol/L)——1—Glucose (mmol/L)11.1———0Pentafraction (g/L)—50——Lactobionic acid (g/L)—35.83——80Lactate (g/L)——28—Raffinose (g/L)—17.83——Adenosine (g/L)—1.34——Allopurinol (g/L)—0.136——Total glutathione (g/L)—0.922——2-Ketoglutarate (mmol/L)———1Histidine (mmol/L)———19830Tryptophan (mmol/L)———2Mannitol (mmol/L)———3060Glutathione3Glutamate20Dextran 40 (g/L)Osmolarity (mosmol/kg)319320370310360Celsior = Celsior solution; HTK = histidine-tryptophan-ketoglutarate solution; ST = St. Thomas' Hospital cardioplegia (the compositions are from the clinically used ST made from original "Sterile Cardioplegia Concentrate", David Bull Laboratories, Mulgrave, Victoria, Australia); UW = University of Wisconsin solution. Open table in a new tab Celsior = Celsior solution; HTK = histidine-tryptophan-ketoglutarate solution; ST = St. Thomas' Hospital cardioplegia (the compositions are from the clinically used ST made from original "Sterile Cardioplegia Concentrate", David Bull Laboratories, Mulgrave, Victoria, Australia); UW = University of Wisconsin solution. As an intracellular type of solution developed in 1980s, University of Wisconsin (UW) solution was initially developed for pancreas transplantation [13Wahlberg J.A. Southard J.H. Belzer F.O. Development of a cold storage solution for pancreas preservation.Cryobiology. 1986; 23: 477-482Crossref PubMed Google Scholar]. The effectiveness of this solution is proved in heart and lung preservation [14Swanson D.K. Pasaoglu I. Berkoff H.A. Southard J.A. Hegge J.O. Improved heart preservation with UW preservation solution.J Heart Transplant. 1988; 7: 456-467PubMed Google Scholar, 15Rinaldi M. Martinelli L. Volpato G. et al.University of Wisconsin solution provides better lung preservation in human lung transplantation.Transplant Proc. 1995; 27: 2869-2871Google Scholar]. However, although UW solution markedly extends preservation time for abdominal organs to tolerate 24 to 48 hours of cold ischemia, the safe time limit for cardiac preservation is only 4 to 6 hours [16Stringham J.C. Southard J.H. Hegge J. Triemstra L. Fields B.L. Belzer F.O. Limitations of heart preservation by cold storage.Transplantation. 1992; 53: 287-294Crossref PubMed Google Scholar]. This crystalloid cardioplegic solution is an extracellular type of solution [5Hearse D.J. Stewart D.A. Braimbridge M.V. Cellular protection during myocardial ischemia the development and characterization of a procedure for the induction of reversible ischemic arrest.Circulation. 1976; 54: 193-202Crossref PubMed Google Scholar]. The subsequent discovery of the efficacy of St. Thomas Hospital (ST) solution in heart storage promoted its application in the field of heart preservation for transplantation [17Wheeldon D. Sharples L. Wallwork J. English T. Donor heart preservation survey.J Heart Lung Transplant. 1992; 11: 986-993PubMed Google Scholar, 18Demertzis S. Wippermann J. Schaper J. et al.University of Wisconsin versus St. Thomas' Hospital solution for human donor heart preservation.Ann Thorac Surg. 1993; 55: 1131-1137Abstract Full Text PDF PubMed Google Scholar]. St. Thomas Hospital solution was widely used for cardioplegia in the 1970s and the 1980s until blood cardioplegia became popular. This solution is still used as crystalloid cardioplegia in some hospitals and also used as a cardioplegic additive for blood cardioplegia. Composition of ST solution varies between its two forms—the original ST solution and ST solution No. 2 (Plegisol). The composition of the ST solution used in our clinical and experimental studies is listed in Table 1. Similar to ST solution, HTK solution was initially developed for cardioplegia. Use of HTK solution was expanded to preservation of the liver, kidney, and pancreas as well as the heart and lung [19Gubernatis G. Dietl K.H. Kemnitz J. et al.Extended cold preservation time (20 hours 20 minutes) of a human liver graft by using cardioplegic HTK solution.Transplant Proc. 1991; 23: 2408-2409PubMed Google Scholar, 20Gschwend J.E. de Petriconi R. Maier S. Kleinschmidt K. Hautmann R.E. Continuous in situ cold perfusion with histidine tryptophan ketoglutarate solution in nephron sparing surgery for renal tumors.J Urol. 1995; 154: 1307-1311Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 21Brandhorst H. Hering B.J. Brandhorst D. et al.Comparison of histidine-tryptophane-ketoglutarate (HTK) and University of Wisconsin (UW) solution for pancreas perfusion before islet isolation, culture and transplantation.Transplant Proc. 1995; 27: 3175-3176Google Scholar, 22Reichenspurner H. Russ C. Uberfuhr P. et al.Myocardial preservation using HTK solution for heart transplantation. A multicenter study.Eur J Cardiothorac Surg. 1993; 7: 414-419Crossref PubMed Google Scholar, 23Couraud L. Baudet E. Velly J.F. Roques X. Martigne C. Gallon P. The Bordeaux Lung and Heart-Lung Transplant GroupLung and heart-lung transplantation for end-stage lung disease.Eur J Cardiothorac Surg. 1990; 4: 318-322Crossref Google Scholar]. The protective effect of HTK solution is based on the high buffering capacity provided by histidine and its low electrolyte content, thus restricting tissue acidosis induced by ischemia [24Gu K. Kin S. Saitoh Y. et al.HTK solution is more effective than UW solution for cardiac preservation.Transplant Proc. 1996; 28: 1906-1907PubMed Google Scholar]. Celsior solution was developed for heart preservation not only as a storage medium but also as a perfusion fluid during initial donor-heart arrest, poststorage graft reimplantation, and early reperfusion [25Menasche P. Termignon J.L. Pradier F. et al.Experimental evaluation of Celsior, a new heart preservation solution.Eur J Cardiothorac Surg. 1994; 8: 207-213Crossref PubMed Google Scholar]. Celsior formulation prevents cell swelling (by mannitol and lactobionate), oxygen-derived free radical injury (by reduced glutathione, histidine, and mannitol), and contracture by enhancement of energy production (glutamate) and limitation of calcium overload (high magnesium content, slight degree of acidosis) [25Menasche P. Termignon J.L. Pradier F. et al.Experimental evaluation of Celsior, a new heart preservation solution.Eur J Cardiothorac Surg. 1994; 8: 207-213Crossref PubMed Google Scholar]. Coronary circulation plays the key role in myocardial perfusion. Injury to the coronary circulation may change the coronary resistance and therefore affect the coronary flow. The reduction of coronary flow may damage myocardial perfusion. During cardiac arrest or heart preservation, the coronary vascular endothelium is immersed in the solution. Although the preservation effect of crystalloid cardioplegic or organ preservation solutions on the endothelial function has been reported [26Evora P.R. Pearson P.J. Schaff H.V. Crystalloid cardioplegia and hypothermia do not impair endothelium-dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries.J Thorac Cardiovasc Surg. 1992; 104: 1365-1374PubMed Google Scholar, 27Ekin S.T. Pearson P.J. Evora P.R. Schaff H.V. One-hour exposure to University of Wisconsin solution does not impair endothelium-dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries.J Heart Lung Transplant. 1993; 12: 624-633PubMed Google Scholar, 28Sorajja P. Cable D.G. Schaff H.V. Hypothermic storage with University of Wisconsin solution preserves endothelial and vascular smooth-muscle function.Circulation. 1997; 96: II-297-II-303Google Scholar], numerous studies provided evidence for endothelial damage after exposure to these solutions. Histologic examination and cell culture approach also revealed that crystalloid hyperkalemic cardioplegic solutions impair the vascular endothelium and reduce the ability of coronary endothelial cells to replicate [29Follet D.M. Buckberg G.D. Mulder D.G. Fonkalsrud E.W. Deleterious effects of crystalloid hyperkalemic cardioplegic solutions on arterial endothelial cells.Surg Forum. 1980; 31: 253Google Scholar, 30Nilsson F.N. Miller V.M. Johnson C.M. Tazelaar H. McGregor C.G. Cardioplegia alters porcine coronary endothelial cell growth and responses to aggregating platelets.J Vasc Res. 1993; 30: 43-52Google Scholar]. As mentioned before, the so-called effect of solutions on coronary endothelium is often mixed with the effects due to other factors combined with the cardioplegia procedure. That is, damage (or protection) to the endothelium may result from not only the solution per se, but also from other components of the procedure. Theoretically, these factors may include the following aspects: 1Direct action of the solutions due to their intrinsic characteristics (the components of the solution)2Adjuncts to the cardioplegic procedure such as hypothermia or the infusion pressure or duration acting both as independent factors and through their interaction with cardioplegic solutions3The effect of ischemia-reperfusion injury4Other factors involved in isolated working heart models or in vivo models when these models are used to study endothelial function. In these studies, the coronary flow is often used as the index of endothelial function but the flow is largely influenced by perfusion pressure [31Katayama O. Amrani M. Ledingham S. et al.Effect of cardioplegia infusion pressure on coronary artery endothelium and cardiac mechanical function.Eur J Cardiothorac Surg. 1997; 11: 751-762Crossref PubMed Scopus (10) Google Scholar, 32Cartier R. Pellerin M. Hollmann C. Pelletier L.C. Effects of pressure and duration of hyperkalemic infusions on endothelial function.Ann Thorac Surg. 1993; 55: 700-705Abstract Full Text PDF PubMed Google Scholar], contractility of the myocardium, and the function of the coronary smooth muscle, among other factors. Due to the influence of these factors, studies suggested that crystalloid-perfused isolated heart is an inappropriate model to interpret the interaction between coronary flow reserve and ischemic injury [33Deng Q. Scicli A.G. Lawton C. Silverman N.A. Coronary flow reserve after ischemia and reperfusion of the isolated heart. Divergent results with crystalloid versus blood perfusion.J Thorac Cardiovasc Surg. 1995; 109: 466-472Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]; use of vascular bed preparation was recommended in the assessment of vascular function [34Saldanha C. Hearse D.J. Cardioplegia and vascular injury. Dissociation of the effects of ischemia from those of the cardioplegic solution.J Thorac Cardiovasc Surg. 1994; 108: 279-290PubMed Google Scholar]. Taken together, the "true" effect of the solutions on the endothelium should be carefully distinguished from other factors in order to identify the possible damaging effect due to the intrinsic characteristics of the solution. In Langendorff preparation of the rat heart [35Saldanha C. Hearse D.J. Coronary vascular responsiveness to 5-hydroxytryptamine before and after infusion of hyperkalemic crystalloid cardioplegic solution in the rat heart. Possible evidence of endothelial damage.J Thorac Cardiovasc Surg. 1989; 98: 783-787PubMed Google Scholar] and an in vivo porcine model of cardiopulmonary bypass [36Sellke F.W. Shafique T. Schoen F.J. Weintraub R.M. Impaired endothelium-dependent coronary microvascular relaxation after cold potassium cardioplegia and reperfusion.J Thorac Cardiovasc Surg. 1993; 105: 52-58PubMed Google Scholar, 37Sellke F.W. Friedman M. Dai H.B. et al.Mechanisms causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion.Cardiovasc Res. 1993; 27: 1925-1932Crossref PubMed Google Scholar, 38Nilsson F.N. Miller V.M. Vanhoutte P.M. McGregor C.G. Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries.J Thorac Cardiovasc Surg. 1991; 102: 923-930PubMed Google Scholar], cold hyperkalemic (25 or 40 mmol/L K+) cardioplegia reduced vasodilatory response to 5-hydroxytryptamine [35Saldanha C. Hearse D.J. Coronary vascular responsiveness to 5-hydroxytryptamine before and after infusion of hyperkalemic crystalloid cardioplegic solution in the rat heart. Possible evidence of endothelial damage.J Thorac Cardiovasc Surg. 1989; 98: 783-787PubMed Google Scholar], adenosine phosphate, calcium ionophore A23187 [36Sellke F.W. Shafique T. Schoen F.J. Weintraub R.M. Impaired endothelium-dependent coronary microvascular relaxation after cold potassium cardioplegia and reperfusion.J Thorac Cardiovasc Surg. 1993; 105: 52-58PubMed Google Scholar, 37Sellke F.W. Friedman M. Dai H.B. et al.Mechanisms causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion.Cardiovasc Res. 1993; 27: 1925-1932Crossref PubMed Google Scholar, 38Nilsson F.N. Miller V.M. Vanhoutte P.M. McGregor C.G. Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries.J Thorac Cardiovasc Surg. 1991; 102: 923-930PubMed Google Scholar], bradykinin, and the α-agonist BHT-920 [38Nilsson F.N. Miller V.M. Vanhoutte P.M. McGregor C.G. Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries.J Thorac Cardiovasc Surg. 1991; 102: 923-930PubMed Google Scholar]. However, ischemia-reperfusion injury was another factor in these studies. The effect of the time of cold ischemic storage with cardioplegic solution was demonstrated [39Budrikis A. Liao Q. Bolys R. Westerlaken B. Steen S. Effects of cardioplegic flushing, storage, and reperfusion on coronary circulation in the pig.Ann Thorac Surg. 1999; 67: 1345-1349Abstract Full Text Full Text PDF Scopus (5) Google Scholar, 40Curro D. Bombardieri G. Barilaro C. et al.Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia.Ann Thorac Surg. 1997; 64: 1354-1359Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Compared with crystalloid cardioplegia, blood cardioplegia preserves the coronary endothelium [38Nilsson F.N. Miller V.M. Vanhoutte P.M. McGregor C.G. Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries.J Thorac Cardiovasc Surg. 1991; 102: 923-930PubMed Google Scholar, 40Curro D. Bombardieri G. Barilaro C. et al.Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia.Ann Thorac Surg. 1997; 64: 1354-1359Abstract Full Text Full Text PDF Scopus (4) Google Scholar, 41Harjula A. Mattila S. Mattila I. et al.Coronary endothelial damage after crystalloid cardioplegia.J Cardiovasc Surg. 1984; 25: 147-152PubMed Google Scholar] and prevents endothelial cells from deformity [40Curro D. Bombardieri G. Barilaro C. et al.Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia.Ann Thorac Surg. 1997; 64: 1354-1359Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. The impact of the ischemic period was also confirmed [40Curro D. Bombardieri G. Barilaro C. et al.Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia.Ann Thorac Surg. 1997; 64: 1354-1359Abstract Full Text Full Text PDF Scopus (4) Google Scholar, 41Harjula A. Mattila S. Mattila I. et al.Coronary endothelial damage after crystalloid cardioplegia.J Cardiovasc Surg. 1984; 25: 147-152PubMed Google Scholar]. However, with prolonged ischemic intervals, the preservative effect of intermittent antegrade warm blood cardioplegia was lost [40Curro D. Bombardieri G. Barilaro C. et al.Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia.Ann Thorac Surg. 1997; 64: 1354-1359Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Numerous studies regarding the effect of heart preservation solutions on the endothelial function have been published. These experimental studies were performed in either hearts or coronary arteries of rat or piglet, aorta of rabbits, endothelial cells of bovine aorta or human saphenous or umbilical veins, but rarely in the coronary arteries of large mammals or humans. The results are largely conflicting because of the variety of experimental methods including the differences of the models, preservation duration and solution temperature, and the index for endothelial function. The results associated with UW and HTK solutions were well summarized in a recent review by Parolari and colleagues [42Parolari A. Rubini P. Cannata A. et al.Endothelial damage during myocardial preservation and storage.Ann Thorac Surg. 2002; 73: 682-690Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] and will not be repeated in this review. It has been reported that loss of endothelium-dependent vasodilatation and nitric oxide (NO) release on bradykinin stimulation after myocardial protection with UW solution in neonatal piglet heart [43Pearl J.M. Laks H. Drinkwater D.C. et al.Loss of endothelium-dependent vasodilatation and nitric oxide release after myocardial protection with University of Wisconsin solution.J Thorac Cardiov
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