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The effect of pinacidil or delivery of Kir6.2/SUR2A genes on hypoxia-reoxygenation induced Ca 2 loading in COS-7 cells. Time course of Fluo-3 fluorescence (A, B) and average concentration of intracellular Ca 2 (A1, B1) in cells exposed to hypoxia (DNP) and reoxygenation (washout) in the presence of 100 M pinacidil (A, A1) or after delivery of Kir6.2/SUR2A genes (B, B1). AU: arbitrary units. (A1) Bars represent mean standard error of the mean (n6); *P0.01.
Source publication
Metabolic injury is a complex process affecting various tissues, with intracellular Ca2+ loading recognized as a common precipitating event leading to cell death. We have recently observed that cells overexpressing recombinant ATP-sensitive K+ (KATP) channel subunits may acquire resistance against metabolic stress. To examine whether, under metabol...
Contexts in source publication
Context 1
... K ATP channel opener, pinacidil (100 M), did not affect intracellular concentration of Ca 2 in untransfected COS-7 cells exposed to chemical hypoxia-reoxygenation protocol (control: 88 10 nM; hypoxia: 86 11 nM; reoxygenation: 228 19 nM, P0.01, n6; Fig. 3A). In cells cotrans- fected with Kir6.2/SUR2A genes, hypoxia-reoxy- genation induced cytosolic Ca 2 loading (control: 95 10 nM; hypoxia: 99 11 nM; reoxygenation: 187 19 nM, P0.01, n6; Fig. 3B). However, in cells cotransfected with Kir6.2/SUR2A, treatment with pinacidil (100 M), an opener of recombi- nant K ATP channels (15,17), prevented ...
Context 2
... 2 in untransfected COS-7 cells exposed to chemical hypoxia-reoxygenation protocol (control: 88 10 nM; hypoxia: 86 11 nM; reoxygenation: 228 19 nM, P0.01, n6; Fig. 3A). In cells cotrans- fected with Kir6.2/SUR2A genes, hypoxia-reoxy- genation induced cytosolic Ca 2 loading (control: 95 10 nM; hypoxia: 99 11 nM; reoxygenation: 187 19 nM, P0.01, n6; Fig. 3B). However, in cells cotransfected with Kir6.2/SUR2A, treatment with pinacidil (100 M), an opener of recombi- nant K ATP channels (15,17), prevented reoxygen- ation-induced Ca 2 loading (control: 99 12 nM; hypoxia: 96 11 nM; reoxygenation: 97 11 nM, P0.05, n6; Fig. 4A). Pinacidil (100 M), when added only during hypoxia, prevented ...
Citations
... Sarcoplasmic reticulum is the major source of Ca 2+ in cardiomyocytes. During ischaemia-reperfusion release of Ca 2+ from sarcoplasmic reticulum occurs leading to intracellular overload (Jovanović et al., 1999;Jovanović and Jovanović, 2001). Ischaemic preconditioning increases calcium uptake and regulating phosphorylation of the ryanodine receptor, reticulum ATPase and phospholamban. ...
A few decades ago, cardiac muscle was discovered to possess signalling pathways that, when activated, protect the myocardium against the damage induced by ischaemia-reperfusion. The ability of cardiac muscle to protect itself against injury has been termed 'cardioprotection'. Many compounds and procedures can trigger cardioprotection including conditionings (exposure to brief episodes of ischaemia-reperfusion to protect against sustained ischaemia-reperfusion), hypoxia, adenosine, acetylcholine, adrenomedullin, angiotensin, bradykinin, catecholamines, endothelin, estrogens, phenylephrine, opioids, testosterone, and many more. These triggers activate many intracellular signalling factors including protein kinases, different enzymes, transcription factors and defined signalling pathways to target structures in mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma to mediate cardioprotection. Although a lot of information about cardioprotection has been acquired, there are still two major outstanding issues to be addressed in the future 1) better understanding of spatio-temporal relationships between signalling elements, and; 2) devising therapeutic strategies against myocardial diseases based on cardioprotective signalling. Further research is required to paint integral picture of cardioprotective signalling and more clinical studies are required to properly test clinical efficacy and safety of potential cardioprotective strategies. Therapies against cardiac diseases based on cardioprotective strategies would be a perfect adjunct to current therapeutic strategies based on restitution of coronary blood flow and regulation of myocardial metabolic demands.
... calcium channel. 2 Deficiency in sarcK ATP channel activity results in dysfunctional intracellular calcium handling with myocardial stress. [9][10][11][12] However, the mechanisms responsible for this calcium mishandling are incompletely resolved. The L-Type calcium channel, phospholamban (PLN), sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA2a), the ryanodine receptor (RyR) and the sodium-calcium exchanger cooperatively regulate cytosolic calcium levels in cardiomyocytes. ...
Background:
Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.
Methods and results:
RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in KCNJ11 expression with ICM. KCNJ11 encodes the Kir6.2 subunit of the cardioprotective KATP channel. Using wild-type mice and kcnj11-deficient (kcnj11-null) mice, we examined the effect of kcnj11 expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in kcnj11-null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in kcnj11-null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in kcnj11-null mice. Despite impaired relaxation, kcnj11-null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca(2+), thereby increasing sarcoendoplasmic reticulum Ca(2+)-mediated calcium reuptake. However, kcnj11-null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca(2+)-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca(2+) function, thereby contributing to diastolic dysfunction.
Conclusions:
KCNJ11 expression is decreased in human ICM. Lack of kcnj11 expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca(2+)-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
... A possible mechanism underlying cytoprotective action of pinacidil and glibenclamide in human oocytes. Cartoon summarizing possible underlying mechanisms mediating pinacidil-(A) and glibenclamide-induced (B) cytoprotection in MII human oocytes based on the findings from the present study as well as findings from previous studies that have investigated K ATP channels in oocytes and other cell types (Brady et al., 1996;Holmuhamedov et al., 1998;Jovanović et al., 1999;Jovanović and Jovanović, 2001;Du et al., 2010). ...
Study question:
Could drugs targeting ATP-sensitive K(+) (KATP) channels prevent any spontaneous increase in intracellular Ca(2+) that may occur in human metaphase II (MII) oocytes under in vitro conditions?
Summary answer:
Pinacidil, a KATP channel opener, and glibenclamide, a KATP channel blocker, prevent a spontaneous increase in intracellular Ca(2+) in human MII oocytes.
What is known already:
The quality of the oocyte and maintenance of this quality during in vitro processing in the assisted reproductive technology (ART) laboratory is of critical importance to successful embryo development and a healthy live birth. Maintenance of Ca(2+) homeostasis is crucial for cell wellbeing and increased intracellular Ca(2+) levels is a well-established indicator of cell stress.
Study design, size, duration:
Supernumerary human oocytes (n = 102) collected during IVF/ICSI treatment that failed to fertilize were used from October 2013 to July 2015. All experiments were performed on mature (MII) oocytes. Dynamics of intracellular Ca(2+) levels were monitored in oocytes in the following experimental groups: (i) Control, (ii) Dimethyl sulfoxide (DMSO; used to dissolve pinacidil, glibenclamide and 2,4-Dinitrophenol (DNP)), (iii) Pinacidil, (iv) Glibenclamide, (v) DNP: an inhibitor of oxidative phosphorylation, (vi) Pinacidil and DNP and (vii) Glibenclamide and DNP.
Participants/materials/settings/methods:
Oocytes were collected under sedation as part of routine treatment at an assisted conception unit from healthy women (mean ± SD) age 34.1 ± 0.6 years, n = 41. Those surplus to clinical use were donated for research. Oocytes were loaded with Fluo-3 Ca(2+)-sensitive dye, and monitored by laser confocal microscopy for 2 h at 10 min intervals. Time between oocyte collection and start of Ca(2+) monitoring was 80.4 ± 2.1 h.
Main results and the role of chance:
Intracellular levels of Ca(2+) increased under in vitro conditions with no deliberate challenge, as shown by Fluo-3 fluorescence increasing from 61.0 ± 11.8 AU (AU = arbitrary units; n = 23) to 91.8 ± 14.0 AU (n = 19; P < 0.001) after 2 h of monitoring. Pinacidil (100 µM) inhibited this increase in Ca(2+) (85.3 ± 12.3 AU at the beginning of the experiment, 81.7 ± 11.0 AU at the end of the experiment; n = 13; P = 0.616). Glibenclamide (100 µM) also inhibited the increase in Ca(2+) (74.7 ± 10.6 AU at the beginning and 71.8 ± 10.9 AU at the end of the experiment; n = 13; P = 0.851. DNP (100 mM) induced an increase in intracellular Ca(2+) that was inhibited by glibenclamide (100 µM; n = 9) but not by pinacidil (100 µM; n = 5).
Limitations, reasons for caution:
Owing to clinical and ethical considerations, it was not possible to monitor Ca(2+) in MII oocytes immediately after retrieval. MII oocytes were available for our experimentation only after unsuccessful IVF or ICSI, which was, on average, 80.4 ± 2.1 h (n = 102 oocytes) after the moment of retrieval. As the MII oocytes used here were those that were not successfully fertilized, it is possible that they may have been abnormal with impaired Ca(2+) homeostasis and, furthermore, the altered Ca(2+) homeostasis might have been associated solely with the protracted incubation.
Wider implications of the findings:
These results show that maintenance of oocytes under in vitro conditions is associated with intracellular increase in Ca(2+), which can be counteracted by drugs targeting KATP channels. As Ca(2+) homeostasis is crucial for contributing to a successful outcome of ART, these results suggest that KATP channel openers and blockers should be tested as drugs for improving success rates of ART.
Study funding/competing interests:
University of Dundee, MRC (MR/K013343/1, MR/012492/1), NHS Tayside. Funding NHS fellowship (Dr Sarah Martins da Silva), NHS Scotland. The authors declare no conflicts of interest.
... In addition, genetic ablation of sarcK ATP in mice hearts has been shown to abolish the cardioprotective effects of preconditioning [96,97] and sarcK ATP knockout hearts also exhibited increased calcium overload and ischemia/reperfusion injury [98]. Also, gene delivery of the sarcK ATP Kir6.2/SUR2A was necessary for improved calcium homeostasis under metabolic stress in a somatic cell line lacking K ATP channels [99]. In summary, evidence suggests that both sarcolemmal and mitochondrial K ATP channels are important mediators of cardioprotection [29]. ...
Cardiac atrial and ventricular arrhythmias are major causes of mortality and morbidity. Ischemic heart disease is the most common cause underlying 1) the development of ventricular fibrillation that results in sudden cardiac death and 2) atrial fibrillation that can lead to heart failure and stroke. Current pharmacological agents for the treatment of ventricular and atrial arrhythmias exhibit limited effectiveness and many of these agents can cause serious adverse effects - including the provocation of lethal ventricular arrhythmias. Sarcolemmal ATP-sensitive potassium channels (sarcK(ATP)) couple cellular metabolism to membrane excitability in a wide range of tissues. In the heart, sarcK(ATP) are activated during metabolic stress including myocardial ischemia, and both the opening of sarcK(ATP) and mitochondrial K(ATP) channels protect the ischemic myocardium via distinct mechanisms. Myocardial ischemia leads to a series of events that promote the generation of arrhythmia substrate eventually resulting in the development of life-threatening arrhythmias. In this review, the possible mechanisms of the anti- and proarrhythmic effects of sarcK(ATP) modulation as well as the influence of pharmacological K(ATP) modulators are discussed. It is concluded that in spite of the significant advances made in this field, the possible cardiovascular therapeutic utility of current sarcK(ATP) channel modulators is still hampered by the lack of chamber-specific selectivity. However, recent insights into the chamber-specific differences in the molecular composition of sarcKATP in addition to already existing cardioselective sarcK(ATP) channel modulators with sarcK(ATP) isoform selectivity holds the promise for the future development of pharmacological strategies specific for a variety of atrial and ventricular arrhythmias.
... In addition to preservation of ATP, K ATP activation can reduce excessive Ca 2+ entry and its destructive sequellae, including arrhythmia, contractile dysfunction and cell death (36). Increase in intracellular Ca 2+ in response to metabolic inhibition-reperfusion is exacerbated in both cardiac myocytes from Kir6.2 −/− animals relative to wild type myocytes, and in untransfected COS-7 cells (relative to cells expressing recombinant K ATP channels) (24, 30, 189,190). The increase in Ca 2+ during metabolic inhibition-reperfusion is correlated with cell death and membrane depolarization, and is significantly blunted by activation of K ATP channels (23, 24, 189,190). ...
... Increase in intracellular Ca 2+ in response to metabolic inhibition-reperfusion is exacerbated in both cardiac myocytes from Kir6.2 −/− animals relative to wild type myocytes, and in untransfected COS-7 cells (relative to cells expressing recombinant K ATP channels) (24, 30, 189,190). The increase in Ca 2+ during metabolic inhibition-reperfusion is correlated with cell death and membrane depolarization, and is significantly blunted by activation of K ATP channels (23, 24, 189,190). Ca 2+ entry by reverse-mode Na+-Ca 2+ exchanger activity is a major contributor to Ca 2+ overload during ischemia-reperfusion (357) and, by reducing membrane depolarization, it is reasonable to predict that K ATP activation will minimize reverse-mode exchanger activity (23). ...
ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.
... A deficit in K ATP channels impairs tolerance to sympathetic surge [134], endurance challenge [64], and hemodynamic load [63, 65, 127]. Genetic disruption of K ATP channels compromises the protective benefits of ischemic preconditioning [46, 113], while overexpression of channel subunits generates a protective phenotype [35, 61, 62]. Mutations that perturb K ATP channel proteins have been linked to increased susceptibility to cardiac pathology in humans. ...
Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype-phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy.
... It is well established that K ATP channels are activated when cardiac cells are challenged with 2.4-dinitrophenol (DNP). This channel activation is cellular self-protective mechanism as it hyperpolarize the membrane, inhibits influx of Ca 2+ and counteracts DNP-induced cellular damage13141516. We have applied perforated patch clamp electrophysiology to test whether infection with AV-SUR2A has any effect on DNP-induced whole cell K + current. Perforated patch whole cell recording does not impair intracellular milieu [17], which allows monitoring the behaviour of K ATP channels-conducted K + current during stress under conditions of intact intracellular environment. ...
... It is traditional view that the activation of K ATP channels shortens action membrane potential resulting in decreased influx of Ca 2+ and prevention of Ca 2+ overload [30]. However, it has been shown that the activation of K ATP channels is protective in cells that do not generate action membrane potential, including diastolic cardiomyocytes141516. More recently, we have suggested that cytoprotection afforded by K ATP channels could also involve a channel activity-independent mechanism [4,5] . ...
Transgenic mice overexpressing SUR2A, a subunit of ATP-sensitive K(+) (K(ATP)) channels, acquire resistance to myocardial ischaemia. However, the mechanism of SUR2A-mediated cytoprotection is yet to be fully understood. Adenoviral SUR2A construct (AV-SUR2A) increased SUR2A expression, number of K(ATP) channels and subsarcolemmal ATP in glycolysis-sensitive manner in H9C2 cells. It also increased K(+) current in response to chemical hypoxia, partially preserved subsarcolemmal ATP and increased cell survival. Kir6.2AFA, a mutant form of Kir6.2 with largely decreased K(+) conductance, abolished the effect of SUR2A on K(+) current, did not affect SUR2A-induced increase in subsarcolemmal ATP and partially inhibited SUR2A-mediated cytoprotection. Infection with 193gly-M-LDH, an inactive mutant of muscle lactate dehydrogenase, abolished the effect of SUR2A on K(+) current, subsarcolemmal ATP and cell survival; the effect of 193gly-M-LDH on cell survival was significantly more pronounced than those of Kir6.2AFA. We conclude that AV-SUR2A increases resistance to metabolic stress in H9C2 cells by increasing the number of sarcolemmal K(ATP) channels and subsarcolemmal ATP.
... It is well established that K ATP channels couple cellular metabolism to electrical activity of the cells. When over-expressed, K ATP channels can confer resistance to metabolic stress in vitro [33] as well as in the forebrain of the transgenic mice in vivo [34]. Opening of K ATP channels when the cellular intracellular ATP/ADP ratio is low during ischemic condition is believed to play a pivotal role in initiating protection by reducing cell membrane excitability during ischemic stress, thereby reducing their metabolic demand and thus allowing the neurons to survive with limited nutrients. ...
To investigate the role of ATP-sensitive potassium (K(ATP)) channels in the neuroprotective effects of a ketogenic diet against cardiac arrest-induced cerebral ischemic brain injury-induced neurodegeneration.
Male Sprague Dawley rats were randomly divided into three groups and were fed with a ketogenic diet for 25 days before being subjected to a cardiac arrest-induced cerebral ischemia for 8 minutes 30 seconds. Four hours before cardiac arrest-induced cerebral ischemia, one group was intracisternally injected with glibenclamide, a plasma membrane K(ATP) channel blocker. The second group was injected with 5-hydroxydecanoate, a mitochondrial K(ATP) channel blocker. The third group was without the pre-treatment with K(ATP) channel antagonist. Nine days after the cardiac arrest, rats were sacrificed. Fluoro-jade (FJ) staining was used to evaluate cerebral ischemic neurodegeneration in the rat brain sections.
The number of FJ-positive degenerating neurons in the CA1 area of the hippocampus, the cerebellum and the thalamic reticular nucleus of the ketogenic diet-fed rats with or without glibenclamide or 5-hydroxydecanoate pre-treatment before cardiac arrest-induced cerebral ischemia is zero.
The results suggest that K(ATP) channels do not play a significant role in the neuroprotective effects of the ketogenic diet against cardiac arrest-induced cerebral ischemic injury-induced neurodegeneration.
... In addition (or in connection) with lactate could be also acidification of the subsarcolemmal regions that would contribute to the K ATP channels opening and, thereby, to cell survival. It has been previously shown, at both native and recombinant levels, that the activation of K ATP channels prevents DNP-induced membrane depolarisation [23,24], which seems to decrease influx of Ca 2+ by inhibiting the activation of voltage gated Ca 2+ channels and preventing intracellular Ca 2+ overload [23,394041. Thus, the activation of K ATP channels is crucial for cytoprotection, but it also seems that a little bit of ATP produced by M-LDH also helps. ...
Muscle form of lactate dehydrogenase (M-LDH), a minor LDH form in cardiomyocytes, physically interacts with ATP-sensitive K+ (K ATP) channel-forming subunits. Here, we have shown that expression of 193gly-M-LDH, an inactive mutant of M-LDH, inhibit regulation of the K ATP channels activity by LDH substrates in embryonic rat heart H9C2 cells. In cells expressing 193gly-M-LDH chemical hypoxia has failed to activate K ATP channels. The similar results were obtained in H9C2 cells expressing Kir6.2AFA, a mutant form of Kir6.2 with largely decreased K+ conductance. Kir6.2AFA has slightly, but significantly, reduced cellular survival under chemical hypoxia while the deleterious effect of 193gly-M-LDH was significantly more pronounced. The levels of total and subsarcolemmal ATP in H9C2 cells were not affected by Kir6.2AFA, but the expression of 193gly-M-LDH led to lower levels of subsarcolemmal ATP during chemical hypoxia. We conclude that M-LDH regulates both the channel activity and the levels of subsarcolemmal ATP and that both mechanism contribute to the M-LDH-mediated cytoprotection.
... On the other hand, more recent work using selective antagonists of sarcolemmal K ATP channels, recombinant channel proteins and transgenic mice lacking sarcolemmal K ATP channels in the heart has provided strong evidence that the activation of this ion channel is cardioprotective. Specifically, it has been shown that (i) coexpression of genes encoding K ATP channels confers resistance against metabolic stress in otherwise stress-sensitive cells (Jovanovi2 et al 1998(Jovanovi2 et al , 1999Crawford et al 2002b), (ii) in mice with a genetically disrupted sarcolemmal K ATP channel the heart is more susceptible to physical stress (Zingman et al 2002), (iii) K ATP channel opener-mediated protection against hypoxia/ischaemia is associated with an effect on cardiac membrane potential and sarcolemmal K ATP channel opening (Jovanovi2 & Jovanovi2 2001a, b;Suzuki et al 2002), (iv) an increase in the number of sarcolemmal K ATP channels increases cardiac resistance to hypoxia/ischaemia (Ranki et al 2001Crawford et al 2003;Brown et al 2005) and (v) ischaemic preconditioning cannot be conferred in transgenic animals lacking sarcolemmal K ATP channels and is associated with sarcolemmal K ATP channel opening and trafficking (Suzuki et al 2002;Budas et al 2004). The mechanism underlying cardioprotection mediated by sarcolemmal K ATP channels is still a matter of discussion. ...
Sarcolemmal ATP-sensitive K(+) (K(ATP)) channels are abundant in cardiac myocytes where they couple the cellular metabolic state with membrane excitability. Structurally, these channels are composed of Kir6.2, a pore-forming subunit, SUR2A, a regulatory subunit, and at least four accessory proteins. The activation of K(ATP) channels occurs during ischaemia to promote cardiac viability under this adverse condition. Age-dependent changes in the myocardial susceptibility to ischaemia have been reported in experimental animals as well as in humans. Recent research has demonstrated that ageing is associated with a decrease in the number of cardiac sarcolemmal K(ATP) channels in hearts from females, but not males. This alteration is likely to be due to an age-dependent decrease in the concentration of circulating estrogens. In the heart, SUR2A is the least expressed protein of all K(ATP) channel-forming proteins. The consequence of this phenomenon is that the level of SUR2A is the main factor controlling the number of sarcolemmal K(ATP) channels. Estrogens specifically up-regulate SUR2A and govern the number of sarcolemmal K(ATP) channels, and this may explain the effect of decreasing estrogen levels on the heart. An age-dependent decrease in the number of sarcolemmal K(ATP) channels generates a cardiac phenotype more sensitive to ischaemia, which seems to be responsible for the ageing-associated decrease in myocardial tolerance to stress that occurs in elderly women.
