Role of Large-conductance Calcium-activated Potassium Channels of Coronary Arteries in Heart Preservation

Han, Jian-Guo; Yang, Qin; Yao, Xiaoqiang; Kwan, Yiu Wa; Shen, Bing; He, Guo‐Wei

doi:10.1016/j.healun.2009.06.011

Cited by 14 publications

(15 citation statements)

References 36 publications

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“…Activation of BK Ca++ channels results in coronary smooth muscle vasodilation (23,13) . Furthermore, activation of BK Ca++ channels with NS1619 (another BK channel activator) demonstrated improved vasodilation in vessels contracted with high K+ cardioplegia (13) . Inhibition of the BKCa++ channels with paxilline greatly reduced the vasodilatory effect of rottlerin, indicating rottlerin also works through smooth muscle BKCa++ channels to improve coronary flow post-CP.…”

Section: Discussionmentioning

confidence: 99%

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Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

et al. 2011

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Background Cardioplegia and cardiopulmonary bypass(CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a PKCδ inhibitor has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin would mitigate deleterious effects associated with CP/CPB. Methods and Results Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10 deg C) cardioplegia (St Thomas II) followed by 30 min normothermic reperfusion. Cardioplegia was delivered every 30 min, for 1 min. Hearts were treated with (CP+R, n=7) or without (CP, n=9) the PKCδ inhibitor, rottlerin (1μM) and/or the BKCa++ channel inhibitor Paxilline (100 nM) supplied in the cardioplegia. Hearts constantly perfused with Krebs-Heinslet buffer served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (LVDP:39±3.8%,±dP/dt: 32±4.4%,-41±5.1% decrease compared to baseline). Treatment with 1uM Rottlerin significantly improved CP-induced cardiac function (LVDP: 20±5.9%, ±dP/dt: 5.2 ±4.5%, -11.6 ± 4.7% decrease versus baseline, (p < .05 CP+R vs CP)). Rottlerin also caused a significant increase in coronary flow post reperfusion (CP 34±4.2% decrease from baseline, vs CP+R 26±9.6% increase over baseline, p=.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction which was restored by rottlerin treatment. The BKCa++ channel inhibitor greatly reduced the majority of beneficial effects associated with Rottlerin. Conclusions Rottlerin significantly improves cardiac performance following cardioplegic arrest via improved cardiomyocyte contraction and coronary perfusion.

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Section: Discussionmentioning

confidence: 99%

“…Rottlerin has been reported as a potent large conductance potassium channel (BK Ca++ ) opener (12) . Opening of BK Ca++ channels is beneficial for post-ischemic alterations in vasomotor activity (13) . In addition, other BK Ca++ channel openers are reported to limit ischemia related mitochondrial Ca ++ overload.…”

Section: Introductionmentioning

confidence: 99%

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

et al. 2011

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“…Casteels and colleagues further showed that the minimal depolarization to evoke contraction of smooth muscle cells isolated from the pulmonary artery was at 9.0 mM KCl (Casteels et al, 1977). Vasoconstriction can also occur from the underlying vascular endothelium, which is electrically connected to smooth muscle (Seiden et al, 2000; Han et al, 2009) (Figure 5). Coronary vascular tone (relaxation/constriction) is regulated by a delicate balance between endothelial vasconstrictive and vasorelaxive factors, which in turn modulate “end-effector” potassium channels (K Ca , Kv, and K ATP channels) and other channels located in underlying vascular smooth muscle of the vessel wall (Figure 6) (Brayden, 1996; Han et al, 2009; Dick and Tune, 2010).…”

Section: Five Areas Of Concern With Hyperkalemic Cardioplegiamentioning

confidence: 99%

“…Vasoconstriction can also occur from the underlying vascular endothelium, which is electrically connected to smooth muscle (Seiden et al, 2000; Han et al, 2009) (Figure 5). Coronary vascular tone (relaxation/constriction) is regulated by a delicate balance between endothelial vasconstrictive and vasorelaxive factors, which in turn modulate “end-effector” potassium channels (K Ca , Kv, and K ATP channels) and other channels located in underlying vascular smooth muscle of the vessel wall (Figure 6) (Brayden, 1996; Han et al, 2009; Dick and Tune, 2010). Furchgott and Zawadzki were the first to show a link between hyperkalemia-induced vasoconstriction and impairment of endothelium-derived nitric oxide (NO) release, and other relaxation factors (Furchgott and Zawadski, 1980).…”

Section: Five Areas Of Concern With Hyperkalemic Cardioplegiamentioning

confidence: 99%

Hyperkalemic cardioplegia for adult and pediatric surgery: end of an era?

Dobson¹,

Faggian²,

Onorati³

et al. 2013

Front. Physiol.

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Despite surgical proficiency and innovation driving low mortality rates in cardiac surgery, the disease severity, comorbidity rate, and operative procedural difficulty have increased. Today's cardiac surgery patient is older, has a “sicker” heart and often presents with multiple comorbidities; a scenario that was relatively rare 20 years ago. The global challenge has been to find new ways to make surgery safer for the patient and more predictable for the surgeon. A confounding factor that may influence clinical outcome is high K+ cardioplegia. For over 40 years, potassium depolarization has been linked to transmembrane ionic imbalances, arrhythmias and conduction disturbances, vasoconstriction, coronary spasm, contractile stunning, and low output syndrome. Other than inducing rapid electrochemical arrest, high K+ cardioplegia offers little or no inherent protection to adult or pediatric patients. This review provides a brief history of high K+ cardioplegia, five areas of increasing concern with prolonged membrane K+ depolarization, and the basic science and clinical data underpinning a new normokalemic, “polarizing” cardioplegia comprising adenosine and lidocaine (AL) with magnesium (Mg2+) (ALM™). We argue that improved cardioprotection, better outcomes, faster recoveries and lower healthcare costs are achievable and, despite the early predictions from the stent industry and cardiology, the “cath lab” may not be the place where the new wave of high-risk morbid patients are best served.

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“…In the whole-cell configuration, BK Ca current sensitive to iberiotoxin was greatly decreased in isolated porcine coronary smooth muscle cells that were exposed to 1-hour ischemia. 65 …”

Section: Bk Ca Channel Under Ischemia-reperfusionmentioning

confidence: 99%

Calcium-activated Potassium Channels in Vasculature in Response to Ischemia-Reperfusion

Yang

Underwood

2012

Journal of Cardiovascular Pharmacology

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Based on the genetic relationship, single-channel conductance, and gating mechanisms, calcium-activated potassium (KCa) channels identified in vasculature can be divided into 3 groups including large-conductance KCa, small, and intermediate conductance KCa. KCa channels in smooth muscle and endothelial cells are essential for the regulation of vascular tone. Vascular dysfunction under ischemia-reperfusion (I-R) or hypoxia-reoxygenation (H-R) conditions is associated with modulations of KCa channels that are attributable to multiple mechanisms. Most studies in this regard relied on the change of relaxation components sensitive to certain channel blockers to indicate the alteration of KCa channels under I-R conditions, which however provided conflicting results for the effect of I-R. The possible mechanisms involved in KCa channel modulation under I-R/H-R include overproduction of reactive oxygen species such as superoxide anion, hydrogen peroxide, and peroxynitrite, increase of intracellular H ion, and lactate accumulation, etc. However, more studies are necessary to further understand the discrepancies in the sensitivity of KCa channels to I-R injury in different vascular beds.

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Role of Large-conductance Calcium-activated Potassium Channels of Coronary Arteries in Heart Preservation

Cited by 14 publications

References 36 publications

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

Hyperkalemic cardioplegia for adult and pediatric surgery: end of an era?

Calcium-activated Potassium Channels in Vasculature in Response to Ischemia-Reperfusion

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Role of Large-conductance Calcium-activated Potassium Channels of Coronary Arteries in Heart Preservation

Cited by 14 publications

References 36 publications

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

Hyperkalemic cardioplegia for adult and pediatric surgery: end of an era?

Calcium-activated Potassium Channels in Vasculature in Response to Ischemia-Reperfusion

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Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK _Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts