BioMed Research International

Volume 2014 (2014), Article ID 324364, 11 pages

http://dx.doi.org/10.1155/2014/324364

Review Article

Protection of Coronary Endothelial Function during Cardiac Surgery: Potential of Targeting Endothelial Ion Channels in Cardioprotection

Qin Yang,1,2,3 Cheuk-Man Yu,¹ Guo-Wei He,3,4 and Malcolm John Underwood⁵

¹Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, and Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

²The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China

³TEDA International Cardiovascular Hospital, Tianjin 300457, China

⁴The Affiliated Hospital of Hangzhou Normal University and Zhejiang University, Hangzhou, Zhejiang 310015, China

⁵Division of Cardiothoracic Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

Received 26 March 2014; Accepted 16 June 2014; Published 13 July 2014

Academic Editor: M.-Saadeh Suleiman

Copyright © 2014 Qin Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K⁺ channels and Ca²⁺-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K⁺ channels, that is, and , and Ca²⁺-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K⁺ and TRP channels for myocardial protection during cardiac surgery.

1. Introduction

Coronary circulation is of vital importance to myocardial perfusion. The vascular endothelium of coronary arteries has been identified as the important organ that locally regulates coronary perfusion and cardiac function by producing vasoactive substances. The compromised function of coronary endothelium during cardiac surgery contributes to the no- or low-reflow phenomenon that ultimately leads to myocardial dysfunction and jeopardizes postoperative cardiac performance. Ischemia-reperfusion (I-R) and the direct contact of coronary endothelium with hyperkalemic solutions during cardioplegic intervention both pose detrimental effects on coronary endothelial function. Ion channels, in particular, potassium (K⁺) channels and calcium- (Ca²⁺-) permeable channels in endothelial cells, are essential to the production and/or function of endothelium-derived vasoactive factors. This review addresses the role of K⁺ and Ca²⁺-permeable channels in endothelial function by focusing on the regulation of vascular tone and summarizes the findings of alterations of these channels under conditions related to cardiac surgery. The potential of targeting these channels for myocardial protection during cardiac surgery is also discussed from the viewpoint of endothelial protection.

2. Endothelial Dysfunction during Cardiac Surgery: Effect of I-R and Cardioplegic Exposure

Endothelium functions to counteract leukocyte adhesion and platelet aggregation to prevent inflammation and thrombosis and actively regulate vascular tone by producing vasoactive substances [1, 2]. During cardiac surgery and cardioplegic intervention, coronary vasculature is inevitably subjected to I-R and hyperkalemic exposure. A considerable body of research shows the susceptibility of vascular endothelium to I-R or hypoxia-reoxygenation (H-R) injury. I-R/H-R activates endothelial cells resulting in neutrophil-endothelium adhesion and inflammation [3]. Activation of endothelial contractile machinery during I-R due to cell reenergization disturbs endothelial barrier function [4]. Moreover, I-R disrupts the balance between endothelium-derived constricting and relaxing factors and thus interrupts blood flow and organ perfusion [5]. The association of I-R and endothelial cell injury in cardiovascular surgery has been discussed in a previous review article by Boyle Jr and colleagues [6].

Cardioplegic and organ preservation solutions were initially designed to protect cardiac myocytes from I-R injury in heart surgery including heart transplantation. However, since endothelial cells differ with myocytes in structure, function, and electrophysiological properties (nonexcitable versus excitable), use of these solutions may not be able to provide protection to coronary endothelium. In fact, although there were studies showing the preservative effect of crystalloid cardioplegic or organ preservation solutions on endothelial function [7, 8], accumulating evidence suggests endothelial damage after exposure to these solutions. Histological examination and cell culture studies showed that crystalloid hyperkalemic cardioplegia impairs vascular endothelium and reduces the replicating ability of coronary endothelial cells [9, 10].

3. Impact of Cardioplegic Intervention on Endothelium-Derived Vasoactive Factors

Cardioplegic intervention interrupts the balance between endothelium-derived constricting and relaxing factors. I-R/H-R increased the production of vasoconstrictors such as endothelin-1 [5]. A large number of studies have revealed the significance of reduction of endothelium-derived relaxing factors (EDRFs), in particular, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), in the disturbance of blood flow in cardiac surgery-related conditions. Mechanisms underlying the impairment of endothelium-dependent vasorelaxation include I-R-induced availability and functional changes of NO and EDHF [11–16] as well as EDHF alterations caused by hyperkalemic exposure [17–20].

3.1. Impact of Cardioplegic Intervention on NO: Role of I-R and Hyperkalemic Exposure

Endothelial function mediated by NO, the major EDRF [21], is impaired during cardiopulmonary surgery. After 1-hour crystalloid cardioplegic arrest, NO release decreased significantly in human coronary vasculature and further decreased upon reperfusion, evidenced by the reduction of NO end-products nitrite and nitrate [22]. Inhibition of NO release after infusion of University of Wisconsin (UW) solution is associated with an attenuated endothelium-dependent vasodilatation [23]. Downregulation of eNOS protein was reported to underlie the loss of NO production caused by cardioplegia-reperfusion [24] and the NO loss after cold ischemic storage in crystalloid cardioplegia could be recovered by chronic oral administration of the NO substrate L-arginine [25]. All these studies demonstrated the unfavorable effect of cardioplegic intervention on endothelial eNOS-NO function. Consistently, we observed NO loss-related endothelial dysfunction and protection of endothelial function provided by eNOS enhancement in porcine coronary arteries which underwent 1 h of hypoxic exposure in St. Thomas cardioplegic (ST) solution and 30 min reoxygenation [26].

3.1.1. I-R and NO

Endothelial I-R injury is closely associated with decrease of NO bioavailability. Myocardial I-R impairs endothelium-dependent NO-mediated relaxation in coronary arteries [27, 28]. Administration of L-arginine preserves postischemic endothelial function in both animals and humans [29, 30]. With measurement of NO using a NO microsensor, we provided direct evidence of NO reduction in coronary arteries in an in vitro I-R model [31].

In addition to the potent vasodilatory effect, NO inhibits platelet aggregation and leukocyte adhesion that is an important component of the endogenous defense mechanism against vascular injury, inflammation, and thrombosis. The loss of NO after myocardial I-R therefore poses profound deleterious effects on the coronary vasculature that further compromises myocardial function.

3.1.2. Hyperkalemic Exposure and NO

Compared to numerous studies of I-R, investigations regarding the impact of hyperkalemic exposure per se on NO function remain limited. We reported that after exposure to crystalloid cardioplegia containing 16–50 mmol/L K⁺, endothelium-dependent vasorelaxations are well preserved in porcine epicardial coronary arteries [32] and neonatal rabbit aorta [33]. In these studies, the cardioplegic solutions were continuously oxygenated and the whole experiment was performed under well-oxygenated condition; therefore, the effect of I-R was completely excluded. It is worth mentioning that, in these studies, endothelium-dependent relaxation was studied in the presence of PGI₂ inhibitor indomethacin; thus, the relaxation involves both NO and EDHF components. However, considering the susceptibility of EDHF to hyperkalemic exposure [17–19], which is addressed in details in the next section, the preserved endothelium-dependent dilator response to a certain extent suggests that hyperkalemic cardioplegic solutions may barely impair NO-related function. Direct measurements of NO demonstrated that NO production in porcine coronary arteries was unaffected by 1 h of exposure to hyperkalemic solution containing 20 mmol/L K⁺ [20]. Whether higher K⁺ concentration and longer exposure may affect endothelial NO production, however, remains unknown.

3.2. Impact of Cardioplegic Intervention on EDHF: Role of I-R and Hyperkalemic Exposure

The contribution of EDHF in vasodilatation increases as vessel size decreases [34, 35], which highlights the importance of this factor in blood flow regulation.

3.2.1. I-R and EDHF

I-R alters EDHF-mediated endothelial function. In a rat I-R model of 2 h occlusion of the middle cerebral artery followed by 24 h reperfusion, the EDHF-mediated dilatation was potentiated [36, 37]. Potentiation of the EDHF-type response was also observed in dog coronary arteries subjected to 1 h of ischemia and 2 h of reperfusion [38]. These findings support the “compensatory or back-up” theory of EDHF mechanism in conditions involving NO loss. However, contradictory evidence is also available showing the deleterious effect of I-R on EDHF-mediated function. For example, in porcine coronary arteries exposed to H-R, the EDHF-mediated relaxation and hyperpolarization were significantly attenuated [15, 39–41]. H-R also blunted the EDHF response in coronary microveins [16]. The reasons of the controversy remain unclear that may include differences in species and vascular beds and differences in experimental settings. The residual NO may also have influence on the result interpretation in studies that only used eNOS inhibitor with no further use of NO scavenger to completely abolish the NO component.

3.2.2. Hyperkalemic Exposure and EDHF

Our laboratory has contributed a great deal to the knowledge of the effect of hyperkalemia on EDHF pathway. With exclusion of the effect of I-R and elimination of the role of PGI₂ and NO, we have demonstrated that hyperkalemic solutions [17–19] and clinically used crystalloid cardioplegia/organ preservation solutions such as ST [42] and UW solutions [43] impair EDHF-mediated function in porcine or human coronary arteries and veins. The depolarizing effect of hyperkalemia on the membrane of vascular smooth muscle cells counteracts and restricts the hyperpolarizing effect of EDHF, which was suggested to be responsible for the attenuated EDHF-mediated vasorelaxation under hyperkalemic cardioplegic exposure [17, 44]. This mechanism also explains the superiority of hyperpolarizing cardioplegia to depolarizing cardioplegia in preservation of EDHF-mediated endothelial function [45].

4. Role of Endothelial Ion Channels in NO and EDHF Pathways

Calcium- (Ca²⁺-) permeable and potassium (K⁺) channels are essential to vascular endothelial function. The importance of Ca²⁺-permeable channels is highlighted by the Ca²⁺-dependency of the synthesis or action of vasoactive agents including relaxing factors. Enzymes responsible for the production of NO and PGI₂ requires an increase in endothelial for activation [46, 47]. The classical EDHF response is initiated by opening of intermediate and small conductance Ca²⁺-activated K⁺ channels (IKCa and SKCa) on the plasma membrane of endothelial cells [48]. In some vasculatures, nonclassical EDHF response mediated by epoxyeicosatrienoic acids (EETs) may also exist. EETs not only activate endothelial IKCa and SKCa but also open myocyte large-conductance KCa (BKCa) to relax vessels [49]. The opening of IKCa and SKCa and the production of EETs also depend on rise in endothelial cells [48, 50].

4.1. Ca²⁺-Permeable TRP Channels

Transient receptor potential (TRP) channels are the most important Ca²⁺-permeable channels in vascular endothelium [51–53]. TRP channels regulate by directly acting as Ca²⁺ entry channels in the plasma membrane or by changing membrane potentials to modulate the driving force for Ca²⁺ entry [54]. Available evidence suggests that, among the six subfamilies of TRP (TRPA, TRPC, TRPV, TRPM, TRPP, and TRPML), canonical and vanilloid TRP (TRPC and TRPV) channels are more significantly involved in the vascular tone regulation. The role of TRPC1, C3, and C4 in Ca²⁺ influx in aortic endothelial cells has been implicated in the relaxant response of mouse aorta to agonists such as carbachol and acetylcholine [55, 56]. The partial involvement of TRPC6 in carbachol-induced relaxation was also observed in the mouse aorta [57]. TRPC3 forms channels endowed with significant constitutive activity [58] and native TRPC3 contributes to constitutive and ATP-dependent Ca²⁺ influx in human coronary artery endothelial cells [59]. Studies of various vascular beds including mesenteric [60], coronary [31, 59], and human internal mammary arteries, a widely used coronary arterial bypass graft [61], have revealed the significance of native TRPC3 in endothelial Ca²⁺ influx and vasorelaxation. Further mechanistic studies demonstrated that TRPC3-mediated Ca²⁺ influx in endothelial cells is necessary to the production of NO and the function of EDHF [31, 62, 63].

Participation of members of TRPV subfamily, in particular V4, was also reported in the control of vascular tone. In TRPV4-deficient mice, endothelium-dependent relaxations in response to acetylcholine and sheer stress were significantly attenuated in small resistance arteries, which was attributed to the inhibition of both NO and EDHF components [64, 65]. In fact, Ca²⁺ influx through TRPV4 has been proposed as a molecular mechanism sensing shear stress that significantly contributes to endothelial mechanotransduction [66]. Recently, in human coronary arterioles, Bubolz and colleagues demonstrated that TRPV4-mediated Ca²⁺ entry is involved in flow-induced vasodilatation. The TRPV4-dependent vasodilator response to arachidonic acid, a potentially important mediator of endothelium-derived hyperpolarizing-related vasodilation, was also reported [67, 68]. The findings that activation of merely a few TRPV4 channels enables local Ca²⁺ signals and causes maximal dilation through IKCa and SKCa activation further highlighted the functional significance of endothelial TRPV4 in vasorelaxation [69]. The physical interaction of TRPV4 with SKCa (KCa 2.3) in endothelial cells provided a structural basis for KCa activation by TRPV4-Ca²⁺ influx [70]. It is suggested that TRPV4-mediated rise in endothelial cells may trigger both NO- and/or EDHF-dependent vasodilatation that seems to be vascular bed-dependent.

4.2. K⁺ Channels

Vascular endothelium expresses a variety of K⁺ channels including inwardly rectifying K⁺ (Kir), ATP-sensitive K⁺  (KATP), voltage-gated K⁺  (KV), and Ca²⁺-activated K⁺  (KCa) channels. The functional significance of Kv channels in endothelium physiology has not been established. Kir channels may serve as sensors for elevated extracellular K⁺ and contribute to K⁺-induced dilation [71] and act as amplifiers of hyperpolarization initiated by the opening of other K⁺ channels, in particular, IKCa and SKCa, to conduct hyperpolarizing signals along endothelial cells [72]. In comparison with Kv and Kir, a considerable body of knowledge has been gained concerning the significance of KATP and KCa channels in endothelial function.

4.2.1. KATP Channel

Patch-clamp studies in knockout mice suggested that endothelial KATP channels are an important component of shear-sensing mechanism in pulmonary microvasculature [73]. Shear stress increases the expression and activity of KATP channels in pulmonary vascular endothelial cells [74]. Previous studies also implicated the functional role of endothelial KATP channels in coronary vasodilatation, although evidence gained largely relied on the effect of pharmacological tools (channel antagonist or/and agonists) that therefore might be indirect. Endothelial KATP channels participate in flow and shear stress-mediated vasodilation [75] and dilations induced by isoflurane [76] and hyperosmolarity [77] in coronary microvessels. In the heart, KATP channels also expressed in endothelial cells of aorta and capillaries [78, 79]. It is believed that hyperpolarization mediated by KATP activation may facilitate Ca²⁺ influx in endothelial cells and thus modulate the production of EDRFs.

4.2.2. KCa Channel

Endothelial IKCa and SKCa channels are of great importance in vascular tone regulation [80–83]. High or low SKCa expression in arteries of SK3 transgenic mouse, respectively, exaggerated or abolished the tonic endothelial dilating influence [84]. In IKCa knockout mice, disruption of the KCa 3.1 gene reduced acetylcholine-induced hyperpolarization in vascular cells which was associated with impairment of vasodilatation and elevation of blood pressure [85]. Intraluminal application of inhibitors of IKCa and SKCa channels blocked EDHF-mediated vasorelaxation [86]. Endothelial membrane hyperpolarization resulting from IKCa and SKCa opening can be conducted along the endothelium via homocellular endothelial gap junctions and transmitted to smooth muscle cells through myoendothelial gap junctions to cause vasodilatation. IKCa predominantly resides in myoendothelial projections whereas SKCa preferentially is located the sites of homocellular endothelial gap junctions and caveolin-rich domains [87–90]. The difference between the subcellular localization of these two subtypes is believed to be a mechanism facilitating efficient signaling transduction within endothelium and between endothelium and smooth muscle. Activation of IKCa and SKCa channels may also induce K⁺ efflux from endothelial cells that elicits hyperpolarization and relaxation of smooth muscle by activating Kir channels and Na⁺-K⁺-ATPase on the smooth muscle membrane [91]. In addition to the significant role in EDHF pathway [82, 83, 86–88, 92–94], activation of IKCa and SKCa channels may also amplify NO production in endothelial cells [95]. It was proposed that the channel opening-induced endothelial hyperpolarization enhances driving force for Ca²⁺ entry, resulting in elevation of and amplification of NO production. The capacity of KCa channels in endothelial modulation, therefore, further highlights the significance of these channels in the regulation of vascular tone.

5. Impact of Cardioplegic Intervention on K⁺ and TRP Channels in Endothelial Cells: Role of I-R and Hyperkalemic Exposure

5.1. Effect of I-R and Hyperkalemic Exposure on KCa Channels

Inactivation of IKCa and/or SKCa channels may contribute to endothelial dysfunction related to cardioplegic arrest/cardiopulmonary bypass in human. Following cardioplegic arrest/cardiopulmonary bypass, coronary arterioles and skeletal muscle arterioles showed significant decreases in vasorelaxant responses to IKCa/SKCa activator and endothelium-dependent vasodilators [96, 97]. In these studies, the alteration of IKCa and SKCa occurred at channel activity level but not at expression level. Alteration of KCa channels under these circumstances may be attributable to both I-R injury and hyperkalemic cardioplegic exposure. Although there are controversial findings regarding the effect of I-R on KCa [98, 99], I-R-induced KCa inhibition was reported repeatedly. Vasorelaxant response to ADP significantly attenuated in goats underwent 1 h occlusion of the left middle cerebral artery followed by 1 h reperfusion and the loss of KCa-EDHF mediation in postischemic vessels was evidenced by the loss of inhibitory effect of IKCa and SKCa channel blockers [100]. Consistently, we showed that EDHF-mediated hyperpolarization and relaxation were impaired in both coronary arteries and veins after 1 h hypoxia and 30 min reoxygenation [15, 16]. Further patch-clamp experiments demonstrated that inhibition of IKCa and SKCa channels is responsible for the compromised EDHF responses after H-R [41].

The effect of hyperkalemia on KCa channels remains poorly studied. We previously demonstrated that the IKCa and SKCa-dependent EDHF responses are impaired by crystalloid hyperkalemic cardioplegia/organ preservation solutions in both coronary and pulmonary vasculatures [101–104]. Although these are not direct evidence of the inhibitory effect of hyperkalemia on endothelial KCa channel activity, given that KCa activation requires rise and membrane depolarization in endothelial cells decreases the driving force for Ca²⁺ entry, suppression of KCa activity therefore may be expected when vascular endothelium is exposed to hyperkalemic cardioplegia/organ preservation solutions.

5.2. Effect of I-R and Hyperkalemic Exposure on KATP Channels

The findings of KATP mediation in the protection offered by preconditioning and postconditioning against endothelial I-R injury may suggest the association of KATP alterations and endothelial dysfunction [105–107]. Pharmacological inhibition of KATP channels reduced or completely blocked the protective effect of preconditioning and postconditioning on endothelium-dependent vasodilation. KATP channel blockade also abolished the protective effect of heat stress on endothelial function in ischemic heart [108]. KATP channel opener KRN₄₈₈₄ mimicked the protective effect of hypoxic preconditioning on the EDHF-mediated relaxation in coronary arteries [40], which may serve as an additional proof of I-R-induced functional disturbance of KATP channels. Further mechanistic investigations established the pivotal role of mitochondria KATP channels in cardioprotection. Opening of the mitochondrial KATP channel is thought to prevent the mitochondrial permeability transition pore from opening, leading to cellular protection from I-R injury in cardiac myocytes and vascular endothelial cells [109, 110].

Supplementation of KATP channel openers such as aprikalim and Nicorandil in hyperkalemic solutions protects EDHF-mediated function in coronary arteries [20, 111, 112]. Although the protection most likely results from the hyperpolarizing effect of KATP channel openers on smooth muscle membrane that counteracts hyperkalemia-induced depolarization thus facilitates EDHF responses, it cannot be ruled out that activation of KATP channels in endothelial cells might as well contribute to the protection of endothelial function. Endothelial KATP channel opening-induced membrane hyperpolarization may increase the driving force for Ca²⁺ influx thus promoting the production of EDRFs including EDHF.

6. Effect of I-R and Hyperkalemic Exposure on TRP Channels

I-R/H-R disturbs intracellular Ca²⁺ homeostasis and Ca²⁺ signaling in vascular endothelial cells. During ischemia, hypoxia/anoxia occurs in conjunction with acidosis and reperfusion is accompanied by increased formation of reactive oxygen species, which all have impact on . For example, changes when extracellular acidosis occurs although the change may vary in different cells. Extracellular acidosis causes Ca²⁺ overload in anoxic endothelial cells from rat coronary artery [113], whereas in porcine aortic endothelial cells, extracellular acidification decreases and inhibits agonist-stimulated production of EDRFs [114]. Suppression of store-operated Ca²⁺ entry via nonselective cation channels was found to be responsible for the decreased Ca²⁺ response in this study [114]. The modulation of store-operated Ca²⁺ entry was also reported in rat cardiac microvascular endothelial cells exposed to H-R [115]. Although these studies did not address by what molecular mechanisms store-operated Ca²⁺ entry is affected, they provided a logical basis for further investigation on the role of TRP channels in I-R-induced disturbance given the significance of TRP channels in store-operated Ca²⁺ entry [52]. In fact, recent studies started to reveal the effects of I-R/H-R on TRP channels and associated vascular endothelial function. In patch-clamp studies of porcine coronary endothelial cells, we, for the first time, demonstrated that H-R suppresses TRPC3 channel activity through inhibiting the membrane translocation of this channel. The inhibition of TRPC3-mediated Ca²⁺ influx is an underlying mechanism of H-R-induced reduction of NO production and attenuation of endothelium-dependent relaxation in coronary arteries [31]. In a mice model of prolonged H-R, preconditioning amplifies EDHF-mediated relaxation with an association of an increase in TRPV4 expression in endothelial cells. Moreover, TRPV4 is involved in eNOS regulation in preconditioning, evidenced by an increase of phosphorylation on eNOS serine 1177 in wide type whereas an inhibition in TRPV4 knockout mice [116].

Changes of membrane potential affects . In endothelial cells depolarized by high K⁺ concentration, reduction of Ca²⁺ influx was observed [117, 118]. However, the mechanism by which endothelial Ca²⁺ channel is affected by hyperkalemia remains poorly studied. Our recent attempt in exploring the impact of hyperkalemia on endothelial Ca²⁺ channels provided the first evidence of the alteration of TRPC3 channels and the functional significance of TRPC3 alteration in hyperkalemia-induced EDHF dysfunction. We demonstrated that Ca²⁺ influx via TRPC3 channels in endothelial cells is reduced by hyperkalemia and activation of TRPC3 restores Ca²⁺ influx and prevents EDHF dysfunction caused by hyperkalemic solutions and clinically used crystalloid cardioplegia/organ preservation solutions such as ST and UW solutions [62].

7. Potential of Targeting K⁺ and TRP Channels for Endothelial Protection during Cardiac Surgery

Advances in understanding the mechanisms of endothelial dysfunction promote the development of strategies for endothelial cell protection. Better preservation of coronary endothelial and myocardial function can be achieved by supplementation of additives in cardioplegic or organ preservation solutions. Earlier studies have provided substantial evidence of the beneficial effect of supplementation of NO precursor L-arginine or NO donors, that is, nitroglycerin in cardioplegia on postischemic ventricular performance and endothelial function [119–121]. The EDHF component is well preserved in cardioplegic solutions containing EET11,12, a possible chemical candidate of EDHF [102, 122].

Earlier attempts including KATP channel openers in hyperkalemic cardioplegia have set a successful example of targeting K⁺ channels for endothelial protection. Hyperkalemia-induced impairment of EDHF function is ameliorated by addition of KATP channel openers such as nicorandil, aprikalim, and KRN₄₈₈₄ in cardioplegic solutions [15, 40, 112]. In addition, cardiac myocytes also benefit from the addition of KATP channel openers. Aprikalim inhibits Na⁺-Ca²⁺ exchange enhanced by hyperkalemia thus preventing overload and improves the contractile function of ventricular myocytes [123]. Addition of the mitochondrial KATP opener diazoxide to heart preservation solution preserves diastolic function and reduces myocardial edema [124]. As to the benefit of KATP channel openers on endothelial function, although hyperpolarization of the smooth muscle cell membrane, the “effector” of EDHF responses is believed to underlie the preservation of EDHF pathway; the activation of KATP channels in endothelial cells might also be involved.

The unveiling of the key role of KCa and TRP channels in endothelial function together with the findings of the alterations of these channels during I-R and hyperkalemic exposure provided scientific basis for the potential of targeting these channels for endothelial protection during cardiac surgery. In an in vitro I-R model, the loss of endothelium-dependent relaxation of coronary arteries can be prevented by activation of IKCa/SKCa and TRPC channels [31, 41]. Pharmacological activation of IKCa and SKCa channels during H-R improves EDHF responses including relaxation and hyperpolarization [41]. A recent review article provided an update on the effectiveness of IKCa/SKCa activators in the treatment of cardiovascular disorders through the improvement of endothelium-derived hyperpolarizations [125]. Meanwhile, the therapeutic potential of activation of endothelial KCa channels to enhance NO availability in conditions associated with NO loss was reviewed by Kerr and colleagues [126].

Recent investigations started to show the potential of targeting endothelial TRP channels for cardiovascular protection, although so far the number of studies remains quite limited. In coronary arteries subjected to H-R, activation of TRPC3 channels in endothelial cells was observed to restore NO production [31]. Most recently, we demonstrated that supplementation of the TRPC3 activator in crystalloid cardioplegia such as ST and histidine-tryptophan-ketoglutarate (HTK) solution preserves TRPC3-mediated Ca²⁺ influx in endothelial cells and improves EDHF-mediated relaxation of coronary arteries [62]. The findings of protective effects of TRPC3 activation on coronary endothelium under H-R and hyperkalemic exposure may therefore shed light on future development of TRPC3-targeting strategies for myocardial protection during cardiac surgery.

Despite advances in the research of endothelial TRP channels, there are still many issues to be resolved, for example, the functional significance of interactions among different TRP isoforms. Whether a pathological condition that inhibits one isoform exerts the same effect on other isoforms or leads to “compensatory” enhancement of the function of others? Whether pharmacological modulation of one isoform has impact on others and changes their role in endothelial function? Answers to these questions are required to fully understand the potential of targeting TRP channels for endothelial cell protection.

In summary, Ca²⁺-permeable TRP and K⁺ channels in endothelial cells are essential to the regulation of vascular tone. Coronary endothelial dysfunction occurs in cardiac surgery that is attributable to I-R injury and hyperkalemic exposure. The functional alteration of endothelial TRP and K⁺ channels during I-R and hyperkalemic exposure renders these channels potential targets for endothelial protection during cardiac surgery.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work was supported by Grants from the Research Grant Council of Hong Kong (CUHK4789/09M & 4774/12M); the National Natural Science Foundation of China 81200123 and 81170148; the CUHK Direct Grant 4054015; the National Basic Research Program of China 2010CB529500; the National Science and Technology Major Project (2013ZX09303004-005); the Tianjin Binhai Key Platform for Creative Research Program (2012-BH110004); the Key Medical Program of Tianjin Binhai New Area Health Bureau (2011BHKZ001, 2012BWKZ008, and 2012BWKY024); and the Tianjin Health Bureau (2012KZ009, 2012KZ010, and 2013KZ009).

References

N. A. Flavahan and P. M. Vanhoutte, “Endothelial cell signaling and endothelial dysfunction,” The American Journal of Hypertension, vol. 8, no. 5, pp. 28S–41S, 1995.

P. O. Bonetti, L. O. Lerman, and A. Lerman, “Endothelial dysfunction: a marker of atherosclerotic risk,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 2, pp. 168–175, 2003.

R. K. Winn, C. Ramamoorthy, N. B. Vedder, S. R. Sharar, and J. M. Harlan, “Leukocyte—endothelial cell interactions in ischemia-reperfusion injury,” Annals of the New York Academy of Sciences, vol. 832, pp. 311–321, 1997.

C. Schäfer, S. Walther, M. Schäfer et al., “Inhibition of contractile activation reduces reoxygenation-induced endothelial gap formation,” Cardiovascular Research, vol. 58, no. 1, pp. 149–155, 2003.

M. Miura, “Regulation and failure of coronary circulation,” Japanese Heart Journal, vol. 37, no. 5, pp. 585–602, 1996.

E. M. Boyle Jr., T. H. Pohlman, C. J. Cornejo, and E. D. Verrier, “Endothelial cell injury in cardiovascular surgery: ischemia-reperfusion,” Annals of Thoracic Surgery, vol. 62, no. 6, pp. 1868–1875, 1996.

P. R. B. Evora, P. J. Pearson, H. V. Schaff, and M. R. Oeltjen, “Crystalloid cardioplegia and hypothermia do not impair endothelium- dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries,” Journal of Thoracic and Cardiovascular Surgery, vol. 104, no. 5, pp. 1365–1374, 1992.

P. Sorajja, D. G. Cable, and H. V. Schaff, “Hypothermic storage with University of Wisconsin solution preserves endothelial and vascular smooth-muscle function,” Circulation, vol. 96, no. 9, pp. II297–II303, 1997.

DM. Follet, GD. Buckberg, DG. Mulder, and EW. Fonkalsrud, “Deleterious effects of crystalloid hyperkalemic cardioplegic solutions on arterial endothelial cells,” Surgical forum, vol. 31, pp. 253–255, 1980.

F. N. Nilsson, V. M. Miller, C. M. Johnson, H. Tazelaar, and C. G. A. McGregor, “Cardioplegia alters porcine coronary endothelial cell growth and responses to aggregating platelets,” Journal of Vascular Research, vol. 30, no. 1, pp. 43–52, 1993.

K. Hashimoto, P. J. Pearson, H. V. Schaff, and R. Cartier, “Endothelial cell dysfunction after ischemic arrest and reperfusion: a possible mechanism of myocardial injury during reflow,” Journal of Thoracic and Cardiovascular Surgery, vol. 102, no. 5, pp. 688–694, 1991.

X. L. Qi, T. L. Nguyen, L. Andries, S. U. Sys, and J. L. Rouleau, “Vascular endothelial dysfunction contributes to myocardial depression in ischemia-reperfusion in the rat,” Canadian Journal of Physiology and Pharmacology, vol. 76, no. 1, pp. 35–45, 1998.

P. A. R. Jorge, M. R. Osaki, E. de Almeida, M. Dalva, and L. C. Neto, “Endothelium-dependent coronary flow in ischemia reperfusion,” Experimental and Toxicologic Pathology, vol. 49, no. 1-2, pp. 147–151, 1997.

D. T. Engelman, M. Watanabe, R. M. Engelman et al., “Constitutive nitric oxide release is impaired after ischemia and reperfusion,” Journal of Thoracic and Cardiovascular Surgery, vol. 110, no. 4 I, pp. 1047–1053, 1995.

Y. Dong, M. Wu, A. P. C. Yim, and G. He, “Hypoxia-reoxygenation, St. Thomas cardioplegic solution, and nicorandil on endothelium-derived hyperpolarizing factor in coronary microarteries,” Annals of Thoracic Surgery, vol. 80, no. 5, pp. 1803–1811, 2005.

Y. Y. Dong, M. Wu, A. P. C. Yim, and G. W. He, “Effect of hypoxia-reoxygenation on endothelial function in porcine cardiac microveins,” Annals of Thoracic Surgery, vol. 81, no. 5, pp. 1708–1714, 2006.

G. W. He, C. Q. Yang, W. F. Graier, and J. A. Yang, “Hyperkalemia alters EDHF-mediated hyperpolarization and relaxation in coronary arteries,” American Journal of Physiology, vol. 271, no. 2, pp. H760–H767, 1996.

G. W. He, “Hyperkalemia exposure impairs EDHF-mediated endothelial function in the human coronary artery,” Annals of Thoracic Surgery, vol. 63, no. 1, pp. 84–87, 1997.

Q. Yang, Y. Liu, W. Zou, A. P. C. Yim, and G. 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,” Journal of Thoracic and Cardiovascular Surgery, vol. 124, no. 2, pp. 361–370, 2002.

Q. Yang, R. Zhang, A. P. C. Yim, and G. He, “Release of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in porcine coronary arteries exposed to hyperkalemia: effect of nicorandil,” Annals of Thoracic Surgery, vol. 79, no. 6, pp. 2065–2071, 2005.

L. J. Ignarro, G. M. Buga, K. S. Wood, R. E. Byrns, and G. Chaudhuri, “Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 24, pp. 9265–9269, 1987.

H. Gohra, Y. Fujimura, K. Hamano et al., “Nitric oxide release from coronary vasculature before, during, and following cardioplegic arrest,” World Journal of Surgery, vol. 23, no. 12, pp. 1249–1253, 1999.

J. M. Pearl, H. Laks, D. C. Drinkwater et al., “Loss of endothelium-dependent vasodilatation and nitric oxide release after myocardial protection with University of Wisconsin solution,” Journal of Thoracic and Cardiovascular Surgery, vol. 107, no. 1, pp. 257–264, 1994.

C. Métais, J. Li, M. Simons, and F. W. Sellke, “Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusion: role of COX-2 expression,” Circulation, vol. 100, no. 19, supplement, pp. II328–II334, 1999.

K. Nakamura, I. Schmidt, C. C. Gray et al., “The effect of chronic L-arginine administration on vascular recovery following cold cardioplegic arrest in rats,” European Journal of Cardio-Thoracic Surgery, vol. 21, no. 4, pp. 753–759, 2002.

H. M. Xue, G. W. He, J. H. Huang, and Q. Yang, “New strategy of endothelial protection in cardiac surgery: use of enhancer of endothelial nitric oxide synthase,” World Journal of Surgery, vol. 34, no. 7, pp. 1461–1469, 2010.

D. D. Ku, “Coronary vascular reactivity after acute myocardial ischemia,” Science, vol. 218, no. 4572, pp. 576–578, 1982.

N. Kaeffer, V. Richard, A. François, F. Lallemand, J. P. Henry, and C. Thuillez, “Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats,” The American Journal of Physiology, vol. 271, no. 3, pp. H842–H849, 1996.

X.-S. Li, Y. Uriuda, Q.-D. Wang, R. Nordlander, P.-O. Sjöquist, and J. Pernow, “Role of L-arginine in preventing myocardial and endothelial injury following ischaemia/reperfusion in the rat isolated heart,” Acta Physiologica Scandinavica, vol. 156, no. 1, pp. 37–44, 1996.

J. Pernow, F. Böhm, E. Beltran, and A. Gonon, “L-Arginine protects from ischemia-reperfusion-induced endothelial dysfunction in humans in vivo,” Journal of Applied Physiology, vol. 95, no. 6, pp. 2218–2222, 2003.

J.-H. Huang, G.-W. He, H.-M. Xue et al., “TRPC3 channel contributes to nitric oxide release: significance during normoxia and hypoxia-reoxygenation,” Cardiovascular Research, vol. 91, no. 3, pp. 472–482, 2011.

G.-W. He, C.-Q. Yang, G. J. Wilson, and I. M. Rebeyka, “Tolerance of epicardial coronary endothelium and smooth muscle to hyperkalemia,” Annals of Thoracic Surgery, vol. 57, no. 3, pp. 682–688, 1994.

G.-W. He, C.-Q. Yang, I. M. Rebeyka, and G. J. Wilson, “Effects of hyperkalemia on neonatal endothelium and smooth muscle,” Journal of Heart and Lung Transplantation, vol. 14, no. 1, pp. 92–101, 1995.

H. Shimokawa, H. Yasutake, K. Fujii et al., “The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation,” Journal of Cardiovascular Pharmacology, vol. 28, no. 5, pp. 703–711, 1996.

H. Tomioka, Y. Hattori, M. Fukao et al., “Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor: importance of processes mediating precontractions,” Journal of Vascular Research, vol. 36, no. 4, pp. 311–320, 1999.

S. P. Marrelli, “Altered endothelial Ca²⁺ regulation after ischemia/reperfusion produces potentiated endothelium-derived hyperpolarizing factor-mediated dilations,” Stroke, vol. 33, no. 9, pp. 2285–2291, 2002.

S. P. Marrelli, W. F. Childres, J. Goddard-Finegold, and R. M. Bryan Jr., “Potentiated EDHF-mediated dilations in the rat middle cerebral artery following ischemia/reperfusion,” in EDHF 2000, P. M. Vanhoutte, Ed., Taylor & Francis, London, UK, 2001.

E. C. H. Chan and O. L. Woodman, “Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries,” British Journal of Pharmacology, vol. 126, no. 4, pp. 925–932, 1999.

L. Ziberna, M. Lunder, J. Kužner, and G. Drevenšek, “Normothermic and hypothermic models for studying the deleterious effects of hypoxia-reoxygenation on EDHF-mediated relaxation in isolated porcine coronary arteries,” Journal of Pharmacological and Toxicological Methods, vol. 59, no. 1, pp. 1–6, 2009.

Z. Ren, Q. Yang, H. S. Floten, A. P. Furnary, A. P. Yim, and G. W. He, “ATP-sensitive potassium channel openers may mimic the effects of hypoxic preconditioning on the coronary artery,” Annals of Thoracic Surgery, vol. 71, no. 2, pp. 642–647, 2001.

Q. Yang, J. H. Huang, Y. B. Man, X. Q. Yao, and G. W. He, “Use of intermediate/small conductance calcium-activated potassium-channel activator for endothelial protection,” Journal of Thoracic and Cardiovascular Surgery, vol. 141, no. 2, pp. 501.e1–510.e1, 2011.

Z. D. Ge and G. W. He, “Altered endothelium-derived hyperpolarizing factor-mediated endothelial function in coronary microarteries by St Thomas' Hospital solution,” Journal of Thoracic and Cardiovascular Surgery, vol. 118, no. 1, pp. 173–180, 1999.

Z. D. Ge and G. W. He, “Comparison of university of Wisconsin and St. Thomas' hospital solutions on endothelium-derived hyperpolarizing factor-mediated function in coronary micro-arteries,” Transplantation, vol. 70, no. 1, pp. 22–31, 2000.

G.-W. He, C.-Q. Yang, and J.-A. Yang, “Depolarizing cardiac arrest and endothelium-derived hyperpolarizing factor-mediated hyperpolarization and relaxation in coronary arteries: the effect and mechanism,” Journal of Thoracic and Cardiovascular Surgery, vol. 113, no. 5, pp. 932–941, 1997.

G.-W. He and C.-Q. Yang, “Superiority of hyperpolarizing to depolarizing cardioplegia in protection of coronary endothelial function,” Journal of Thoracic and Cardiovascular Surgery, vol. 114, no. 4, pp. 643–650, 1997.

R. Govers and T. J. Rabelink, “Cellular regulation of endothelial nitric oxide synthase,” The American Journal of Physiology: Renal Physiology, vol. 280, no. 2, pp. F193–F206, 2001.

E. Millanvoye-Van Brussel, M. David-Dufilho, T. D. Pham, L. Iouzalen, and M. A. Devynck, “Regulation of arachidonic acid release by calcium influx in human endothelial cells,” Journal of Vascular Research, vol. 36, no. 3, pp. 235–244, 1999.

G. Edwards, M. Félétou, and A. H. Weston, “Endothelium-derived hyperpolarising factors and associated pathways: a synopsis,” Pflügers Archiv—European Journal of Physiology, vol. 459, no. 6, pp. 863–879, 2010.

A. H. Weston, M. Félétou, P. M. Vanhoutte, J. R. Falck, W. B. Campbell, and G. Edwards, “Bradykinin-induced, endothelium-dependent responses in porcine coronary arteries: involvement of potassium channel activation and epoxyeicosatrienoic acids,” British Journal of Pharmacology, vol. 145, no. 6, pp. 775–784, 2005.

B. T. Larsen, D. X. Zhang, and D. D. Gutterman, “Epoxyeicosatrienoic acids, TRP channels, and intracellular Ca²⁺ in the vasculature: An endothelium-derived endothelium-hyperpolarizing factor?” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2496–2498, 2007.

B. Nilius and G. Droogmans, “Ion channels and their functional role in vascular endothelium,” Physiological Reviews, vol. 81, no. 4, pp. 1415–1459, 2001.

B. Nilius, G. Droogmans, and R. Wondergem, “Transient receptor potential channels in endothelium: solving the calcium entry puzzle?” Endothelium, vol. 10, no. 1, pp. 5–15, 2003.

X. Yao and C. J. Garland, “Recent developments in vascular endothelial cell transient receptor potential channels,” Circulation Research, vol. 97, no. 9, pp. 853–863, 2005.

B. Minke, “TRP channels and Ca²⁺ signaling,” Cell Calcium, vol. 40, no. 3, pp. 261–275, 2006.

M. Y. Kochukov, A. Balasubramanian, R. C. Noel, and S. P. Marrelli, “Role of TRPC1 and TRPC3 channels in contraction and relaxation of mouse thoracic aorta,” Journal of Vascular Research, vol. 50, no. 1, pp. 11–20, 2012.

M. Freichel, S. H. Suh, A. Pfeifer et al., “Lack of an endothelial store-operated Ca²⁺ current impairs agonist-dependent vasorelaxation in TRP4-/-mice,” Nature Cell Biology, vol. 3, no. 2, pp. 121–127, 2001.

F. Loga, K. Domes, M. Freichel et al., “The role of cGMP/cGKI signalling and Trpc channels in regulation of vascular tone,” Cardiovascular Research, vol. 100, no. 2, pp. 280–287, 2013.

M. Trebak, G. Vazquez, G. S. J. Bird, and J. W. Putney Jr., “The TRPC3/6/7 subfamily of cation channels,” Cell Calcium, vol. 33, no. 5-6, pp. 451–461, 2003.

K. Smedlund and G. Vazquez, “Involvement of native TRPC3 proteins in ATP-dependent expression of VCAM-1 and monocyte adherence in coronary artery endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 2049–2055, 2008.

C. L. Liu, Y. Huang, C. Y. Ngai, Y. K. Leung, and X. Q. Yao, “TRPC3 is involved in flow- and bradykinin-induced vasodilation in rat small mesenteric arteries,” Acta Pharmacologica Sinica, vol. 27, no. 8, pp. 981–990, 2006.

G. Gao, X. Y. Bai, C. Xuan et al., “Role of TRPC3 channel in human internal mammary artery,” Archives of Medical Research, vol. 43, no. 6, pp. 431–437, 2012.

Q. Yang, J. H. Huang, X. Q. Yao, M. J. Underwood, and C. M. Yu, “Activation of TRPC channels preserves Ca²⁺ entry and EDHF function in vitro in porcine coronary endothelial cells and coronary arteries under conditions of hyperkalemia,” The Journal of Thoracic and Cardiovascular Surgery, 2014.

S. Senadheera, Y. Kim, T. H. Grayson et al., “Transient receptor potential canonical type 3 channels facilitate endothelium-derived hyperpolarization-mediated resistance artery vasodilator activity,” Cardiovascular Research, vol. 95, no. 4, pp. 439–447, 2012.

D. X. Zhang, S. A. Mendoza, A. H. Bubolz et al., “Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo,” Hypertension, vol. 53, no. 3, pp. 532–538, 2009.

S. A. Mendoza, J. Fang, D. D. Gutterman et al., “TRPV4-mediated endothelial Ca²⁺ influx and vasodilation in response to shear stress,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 298, no. 2, pp. H466–H476, 2010.

V. Hartmannsgruber, W. Heyken, M. Kacik et al., “Arterial response to shear stress critically depends on endothelial TRPV4 expression,” PLoS ONE, vol. 2, no. 9, article e827, 2007.

A. H. Bubolz, S. A. Mendoza, X. Zheng et al., “Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: Role of Ca2+ entry and mitochondrial ROS signaling,” American Journal of Physiology - Heart and Circulatory Physiology, vol. 302, no. 3, pp. H634–H642, 2012.

X. Zheng, N. S. Zinkevich, D. Gebremedhin et al., “Arachidonic acid-induced dilation in human coronary arterioles: convergence of signaling mechanisms on endothelial TRPV4-mediated Ca²⁺ entry,” Journal of the American Heart Association, vol. 2, no. 3, Article ID e000080, 2013.

S. K. Sonkusare, A. D. Bonev, J. Ledoux et al., “Elementary Ca²⁺ signals through endothelial TRPV4 channels regulate vascular function,” Science, vol. 336, no. 6081, pp. 597–601, 2012.

X. Ma, J. Du, P. Zhang et al., “Functional role of TRPV4-KCa2.3 signaling in vascular endothelial cells in Normal and streptozotocin-induced diabetic rats,” Hypertension, vol. 62, no. 1, pp. 134–139, 2013.

G. J. Crane, S. D. Walker, K. A. Dora, and C. J. Garland, “Evidence for a differential cellular distribution of inward rectifier K channels in the rat isolated mesenteric artery,” Journal of Vascular Research, vol. 40, no. 2, pp. 159–168, 2003.

W. F. Jackson, “Potassium channels in the peripheral microcirculation,” Microcirculation, vol. 12, no. 1, pp. 113–127, 2005.

S. Chatterjee, I. Levitan, Z. Wei, and A. B. Fisher, “ channels are an important component of the shear-sensing mechanism in the pulmonary microvasculature,” Microcirculation, vol. 13, no. 8, pp. 633–644, 2006.

S. Chatterjee, A. B. Al-Mehdi, I. Levitan, T. Stevens, and A. B. Fisher, “Shear stress increases expression of a KATP channel in rat and bovine pulmonary vascular endothelial cells,” The American Journal of Physiology—Cell Physiology, vol. 285, no. 4, pp. C959–C967, 2003.

L. Kuo and J. D. Chancellor, “Adenosine potentiates flow-induced dilation of coronary arterioles by activating KATP channels in endothelium,” American Journal of Physiology: Heart and Circulatory Physiology, vol. 269, no. 2, pp. H541–H549, 1995.

A. K. Gamperl, T. W. Hein, L. Kuo, and B. A. Cason, “Isoflurane-induced dilation of porcine coronary microvessels is endothelium dependent and inhibited by glibenclamide,” Anesthesiology, vol. 96, no. 6, pp. 1465–1471, 2002.

H. Ishizaka and L. Kuo, “Endothelial ATP-sensitive potassium channels mediate coronary microvascular dilation to hyperosmolarity,” The American Journal of Physiology, vol. 273, no. 1, pp. H104–H112, 1997.

D. Janigro, G. A. West, E. L. Gordon, and H. R. Winn, “ATP-sensitive K⁺ channels in rat aorta and brain microvascular endothelial cells,” The American Journal of Physiology, vol. 265, no. 3, pp. C812–C821, 1993.

M. Mederos Y Schnitzler, C. Derst, J. Daut, and R. Preisig-Müller, “ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart,” Journal of Physiology, vol. 525, no. 2, pp. 307–317, 2000.

S. M. Marchenko and S. O. Sage, “Calcium-activated potassium channels in the endothelium of intact rat aorta,” Journal of Physiology, vol. 492, no. 1, pp. 53–60, 1996.

R. Köhler, C. Degenhardt, M. Kühn, N. Runkel, M. Paul, and J. Hoyer, “Expression and function of endothelial Ca²⁺-activated K⁺ channels in human mesenteric artery: a single-cell reverse transcriptase-polymerase chain reaction and electrophysiological study in situ,” Circulation Research, vol. 87, no. 6, pp. 496–503, 2000.

R. Bychkov, M. P. Burnham, G. R. Richards et al., “Characterization of a charybdotoxin-sensitive intermediate conductance Ca²⁺-activated K⁺ channel in porcine coronary endothelium: relevance to EDHF,” British Journal of Pharmacology, vol. 137, no. 8, pp. 1346–1354, 2002.

M. P. Burnham, R. Bychkov, M. Félétou et al., “Characterization of an apamin-sensitive small-conductance Ca²⁺-activated K⁺ channel in porcine coronary artery endothelium: relevance to EDHF,” British Journal of Pharmacology, vol. 135, no. 5, pp. 1133–1143, 2002.

M. S. Taylor, A. D. Bonev, T. P. Gross et al., “Altered expression of small-conductance Ca²⁺-activated K⁺ (SK3) channels modulates arterial tone and blood pressure,” Circulation Research, vol. 93, no. 2, pp. 124–131, 2003.

H. Si, W. T. Heyken, S. E. Wölfle et al., “Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca²⁺-activated K⁺ channel,” Circulation Research, vol. 99, no. 5, pp. 537–544, 2006.

J. M. Doughty, F. Plane, and P. D. Langton, “Charybdotoxin and apamin block EDHF in rat mesenteric artery if selectively applied to the endothelium,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 276, no. 3, pp. H1107–H1112, 1999.

S. L. Sandow, C. B. Neylon, M. X. Chen, and C. J. Garland, “Spatial separation of endothelial small- and intermediate-conductance calcium-activated potassium channels (KCa) and connexins: possible relationship to vasodilator function?” Journal of Anatomy, vol. 209, no. 5, pp. 689–698, 2006.

M. Absi, M. P. Burnham, A. H. Weston, E. Harno, M. Rogers, and G. Edwards, “Effects of methyl β-cyclodextrin on EDHF responses in pig and rat arteries; association between SK Ca channels and caveolin-rich domains,” British Journal of Pharmacology, vol. 151, no. 3, pp. 332–340, 2007.

K. A. Dora, N. T. Gallagher, A. McNeish, and C. J. Garland, “Modulation of endothelial cell KCa3.1 channels during endothelium-derived hyperpolarizing factor signaling in mesenteric resistance arteries,” Circulation Research, vol. 102, no. 10, pp. 1247–1255, 2008.

J. Ledoux, M. S. Taylor, A. D. Bonev et al., “Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 28, pp. 9627–9632, 2008.

G. Edwards, K. A. Dora, M. J. Gardener, C. J. Garland, and A. H. Weston, “K⁺ is an endothelium-derived hyperpolarizing factor in rat arteries,” Nature, vol. 396, no. 6708, pp. 269–272, 1998.

H. Hashitani and H. Suzuki, “K⁺ channels which contribute to the acetylcholine-induced hyperpolarization in smooth muscle of the guinea-pig submucosal arteriole,” Journal of Physiology, vol. 501, no. 2, pp. 319–329, 1997.

Z. D. Ge, X. H. Zhang, P. C. Chin-Wan Fung, and G. W. He, “Endothelium-dependent hyperpolarization and relaxation resistance to N(G)-nitro-L-arginine and indomethacin in coronary circulation,” Cardiovascular Research, vol. 46, no. 3, pp. 547–556, 2000.

Q. Yang, Z.-D. Ge, C.-Q. Yang, Y. Huang, and G.-W. He, “Bioassay of endothelium-derived hyperpolarizing factor with abolishment of nitric oxide and the role of gap junctions in the porcine coronary circulation,” Drug Development Research, vol. 58, no. 1, pp. 99–110, 2003.

J. Sheng and A. P. Braun, “Small- and intermediate-conductance Ca²⁺-activated K⁺ channels directly control agonist-evoked nitric oxide synthesis in human vascular endothelial cells,” American Journal of Physiology: Cell Physiology, vol. 293, no. 1, pp. C458–C467, 2007.

J. Feng, Y. Liu, R. T. Clements et al., “Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest,” Circulation, vol. 118, no. 14, pp. S46–S51, 2008.

Y. Liu, E. W. Sellke, J. Feng et al., “Calcium-activated potassium channels contribute to human skeletal muscle microvascular endothelial dysfunction related to cardiopulmonary bypass,” Surgery, vol. 144, no. 2, pp. 239–244, 2008.

M. J. Cipolla and J. A. Godfrey, “Effect of hyperglycemia on brain penetrating arterioles and cerebral blood flow before and after ischemia/reperfusion,” Translational Stroke Research, vol. 1, no. 2, pp. 127–134, 2010.

M. J. Cipolla, J. Smith, M. M. Kohlmeyer, and J. A. Godfrey, “SK Ca and IK Ca channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles effect of ischemia and reperfusion,” Stroke, vol. 40, no. 4, pp. 1451–1457, 2009.

A. Sánchez, N. Fernández, L. Monge et al., “Goat cerebrovascular reactivity to ADP after ischemia-reperfusion. Role of nitric oxide, prostanoids and reactive oxygen species,” Brain Research, vol. 1120, no. 1, pp. 114–123, 2006.

G. W. He, Z. D. Ge, A. P. C. Yim, Q. Yang, and R. Zhang, “Electrophysiologic and mechanical evidence of superiority of hyperpolarizing versus depolarizing cardioplegia in protection of endothelium-derived hyperpolarizing factor-mediated endothelial function: a study in coronary resistance arteries,” Journal of Thoracic and Cardiovascular Surgery, vol. 127, no. 6, pp. 1773–1780, 2004.

Q. Yang, R. Zhang, A. P. C. Yim, and G. He, “Effect of 11,12-epoxyeicosatrienoic acid as an additive to st. thomas’ cardioplegia and university of wisconsin solutions on endothelium-derived hyperpolarizing factor–mediated function in coronary microarteries: influence of temperature and time,” The Annals of Thoracic Surgery, vol. 76, no. 5, pp. 1623–1630, 2003.

Q. Yang, R.-Z. Zhang, A. P. C. Yim, and G.-W. He, “Histidine-tryptophan-ketoglutarate solution maximally preserves endothelium-derived hyperpolarizing factor-mediated function during heart preservation: comparison with University of Wisconsin solution,” The Journal of Heart and Lung Transplantation, vol. 23, no. 3, pp. 352–359, 2004.

R. Z. Zhang, Q. Yang, A. P. Yim, and G. W. He, “Alteration of cellular electrophysiologic properties in porcine pulmonary microcirculation after preservation with University of Wisconsin and Euro-Collins solutions,” Annals of Thoracic Surgery, vol. 77, no. 6, pp. 1944–1950, 2004.

M. Ma̧czewski and A. Berȩsewicz, “The role of adenosine and ATP-sensitive potassium channels in the protection afforded by ischemic preconditioning against the post-ischemic endothelial dysfunction in guinea-pig hearts,” Journal of Molecular and Cellular Cardiology, vol. 30, no. 9, pp. 1735–1747, 1998.

J. F. Bouchard and D. Lamontagne, “Mechanisms of protection afforded by preconditioning to endothelial function against ischemic injury,” The American Journal of Physiology: Heart and Circulatory Physiology, vol. 271, no. 5, pp. H1801–H1806, 1996.

M. W. Broadhead, R. K. Kharbanda, M. J. Peters, and R. J. MacAllister, “ channel activation induces ischemic preconditioning of the endothelium in humans in vivo,” Circulation, vol. 110, no. 15, pp. 2077–2082, 2004.

M. Joyeux, J. Bouchard, D. Lamontagne, D. Godin-Ribuot, and C. Ribuot, “Heat stress-induced protection of endothelial function against ischaemic injury is abolished by ATP-sensitive potassium channel blockade in the isolated rat heart,” British Journal of Pharmacology, vol. 130, no. 2, pp. 345–350, 2000.

P. Ferdinandy, R. Schulz, and G. F. Baxter, “Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning,” Pharmacological Reviews, vol. 59, no. 4, pp. 418–458, 2007.

M. I. Okorie, D. D. Bhavsar, D. Ridout et al., “Postconditioning protects against human endothelial ischaemiareperfusion injury via subtype-specific K ATP channel activation and is mimicked by inhibition of the mitochondrial permeability transition pore,” European Heart Journal, vol. 32, no. 10, pp. 1266–1274, 2011.

G. W. He, “Potassium-channel opener in cardioplegia may restore coronary endothelial function,” Annals of Thoracic Surgery, vol. 66, no. 4, pp. 1318–1322, 1998.

C. Long, W. Li, D. Lin, and J. Yang, “Effect of potassium-channel openers on the release of endothelium-derived hyperpolarizing factor in porcine coronary arteries stored in cold hyperkalemic solution,” Journal of Extra-Corporeal Technology, vol. 34, no. 2, pp. 125–129, 2002.

Y. Ladilov, C. Schäfer, A. Held, M. Schäfer, T. Noll, and H. M. Piper, “Mechanism of Ca²⁺ overload in endothelial cells exposed to simulated ischemia,” Cardiovascular Research, vol. 47, no. 2, pp. 394–403, 2000.

M. Asai, K. Takeuchi, M. Saotome et al., “Extracellular acidosis suppresses endothelial function by inhibiting store-operated Ca²⁺ entry via non-selective cation channels,” Cardiovascular Research, vol. 83, no. 1, pp. 97–105, 2009.

S. C. Peters and H. M. Piper, “Reoxygenation-induced Ca²⁺ rise is mediated via Ca²⁺ influx and Ca²⁺ release from the endoplasmic reticulum in cardiac endothelial cells,” Cardiovascular Research, vol. 73, no. 1, pp. 164–171, 2007.

G. Rath, J. Saliez, G. Behets et al., “Vascular hypoxic preconditioning relies on TRPV4-dependent calcium influx and proper intercellular gap junctions communication,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 9, pp. 2241–2249, 2012.

R. E. Laskey, D. J. Adams, A. Johns, G. M. Rubanyi, and C. van Breemen, “Membrane potential and Na⁺-K⁺ pump activity modulate resting and bradykinin-stimulated changes in cytosolic free calcium in cultured endothelial cells from bovine atria,” The Journal of Biological Chemistry, vol. 265, no. 5, pp. 2613–2619, 1990.

W. P. Schilling, L. Rajan, and E. Strobl-Jager, “Characterization of the bradykinin-stimulated calcium influx pathway of cultured vascular endothelial cells. Saturability, selectivity, and kinetics,” Journal of Biological Chemistry, vol. 264, no. 22, pp. 12838–12848, 1989.

H. Sato, Z. Q. Zhao, D. S. McGee, M. W. Williams, J. W. Hammon Jr., and J. Vinten-Johansen, “Supplemental l-arginine during cardioplegic arrest and reperfusion avoids regional postischemic injury,” The Journal of Thoracic and Cardiovascular Surgery, vol. 110, no. 2, pp. 302–314, 1995.

A. M. Lefer, “Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy,” The Annals of Thoracic Surgery, vol. 60, no. 3, pp. 847–851, 1995.

P. P. McKeown, J. S. McClelland, D. K. Bone et al., “Nitroglycerin as an adjunct to hypothermic hyperkalemic cardioplegia,” Circulation, vol. 68, no. 3, pp. II107–II111, 1983.

W. Zou, Q. Yang, A. P. C. Yim, and G. He, “Epoxyeicosatrienoic acids (EET11,12) may partially restore endothelium-derived hyperpolarizing factor-mediated function in coronary microarteries,” Annals of Thoracic Surgery, vol. 72, no. 6, pp. 1970–1976, 2001.

H. Y. Li, S. Wu, G. W. He, and T. M. Wong, “Aprikalim reduces the Na⁺-Ca2⁺ exchange outward current enhanced by hyperkalemia in rat ventricular myocytes,” Annals of Thoracic Surgery, vol. 73, no. 4, pp. 1253–1259, 2002.

E. Kevelaitis, A. Oubenaissa, C. Mouas, J. Peynet, and P. Menasché, “Opening of mitochondrial potassium channels: a new target for graft preservation strategies?” Transplantation, vol. 70, no. 4, pp. 576–578, 2000.

H. Wulff and R. Köhler, “Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets,” Journal of Cardiovascular Pharmacology, vol. 61, no. 2, pp. 102–112, 2013.

P. M. Kerr, R. Tam, D. Narang et al., “Endothelial calcium-activated potassium channels as therapeutic targets to enhance availability of nitric oxide,” Canadian Journal of Physiology and Pharmacology, vol. 90, no. 6, pp. 739–752, 2012.