Activation Of ATP-dependent Potassium Channels Research Articles

Meta-Analysis of the Efficacy of Levosimendan in the Treatment of Severe Sepsis Complicated with Septic Cardiomyopathy.

Sepsis is a medical condition characterized by acute organ dysfunction and uncontrolled inflammation. Organ dysfunction in sepsis is the primary cause of mortality in patients with myocardial dysfunction. Levosimendan is a vasodilating and inotropic agent used in patients with acute heart failure and has resulted in decreased morbidity and mortality in these patients. Our main objective is to examine levosimendan's efficacy in treating severe sepsis complicated with septic cardiomyopathy. We systematically searched five databases, PubMed, Web of Science, Embase, Cochrane Library and BioMed Central, for articles and publications from their inception to 2023. Our study adopted the PICOS approach in identifying suitable publications during the systematic search. Inclusion criteria included randomized, controlled trials utilizing levosimendan in adult patients diagnosed with septic shock or severe sepsis. We excluded non-English publications and non-randomized controlled trials. The Newcastle-Ottawa scale (NOS) scale was used to assess the methodological quality, while the risk of bias was assessed through the Cochrane Risk of bias tool. All statistical analyses were performed using RevMan version 5.4. Eight studies met the eligibility criteria and were included in the analysis. There was a statistically significant positive effect on cardiac input in patients treated with levosimendan compared to those treated with dobutamine (p < 0.001). Similarly, there were positive effects on left ventricular ejection fraction (LVEF) (p < 0.001) and left ventricular stroke work index (LVSWI) (p < 0.001). We observed a significant reduction in mortality (p < 0.01) and serum levels of lactic acid (p < 0.01). Levosimendan is a calcium sensitizer associated with an influx of calcium ions and activation of ATP-dependent potassium channels that increases myocardial contractility contractions, enhances vasodilation and improves oxygen supply to the cells and tissues. Levosimendan is highly efficacious and safe in the management of sepsis and sepsis-induced cardiomyopathy.

Metformin effect in models of inflammation is associated with activation of ATP-dependent potassium channels and inhibition of tumor necrosis factor-α production

Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1h) per os (p.o.) administration of metformin (250, 500 or 1000mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600μg) and also the pleurisy induced by this stimulus (200μg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1h) the inflammatory stimulus. Metformin (1000mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10mg/kg, intraperitoneal) or cyproheptadine (5 or 10mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.

Interaction between Hydrogen Sulfide and Muscarinic Receptors in the Regulation of Contractility of the Mouse Atrium

Hydrogen sulfide (H2S) is an endogenously synthesized gaseous transmitter that participates in the regulation of the cardiovascular system and has a cardioprotective effect under ischemia–reperfusion conditions. Here, we studied possible mechanisms of the interaction of H2S and muscarinic acetylcholine receptors in the regulation of mice atrium contractility in the isometric conditions. We show that sodium hydrosulfide (NaHS), an exogenous donor of H2S, caused dose-dependent and reversible depression of the contractile force in the concentration range from 1 μM to 5 mM. The negative inotropic effect of NaHS did not change after the activation of muscarinic acetylcholine receptors by carbachol. However, we observed that the negative inotropic effect of carbachol increased after preliminary application of NaHS. The application of the reducing agent dithiothreitol did not change the effects of carbachol, which indicated that the effects of NaHS was not related to a direct action on the disulfide bonds of the receptor’s protein subunits. The increased effects of carbachol after NaHS application were not prevented by the inhibition of intracellular signaling pathway that mediated activation of M-cholinergic receptors, including adenylate cyclase, guanylate cyclase, and NO-synthase. However, an increase in the carbachol negative inotropic effect was not observed when ATP-dependent potassium channels were inhibited by glibenclamide. In its turn, activation of ATPdependent potassium channels by diazoxide resulted in an increase in carbachol negative inotropic action in the atrial myocardium of mice similar to the effect of NaHS. Our data indicate that the enhanced negative inotropic effect of carbachol under the action of H2S in the mouse atrium was mediated by the activation of ATP-dependent potassium channels.

Role of Potassium Channels in the Effects of Hydrogen Sulfide on Contractility of Gastric Smooth Muscle Cells in Rats

The effect of sodium hydrosulfide (NaHS), a hydrogen sulfide (H2S) donor, on spontaneous contractile activity of rat gastric smooth muscle cells was analyzed. Experiments were conducted on gastric stripes under conditions of isometric contraction. It was shown that NaHS has a biphasic effect on spontaneous contractile activity, increasing tonic tension and the amplitude of phasic contractions within the first minutes since application. This initial phase is followed by a decrease in amplitude, basal tone, and frequency of spontaneous contractions. The inhibitory effect of NaHS was dose-dependent at concentrations from 10 to 600 μM. Preliminary application of tetraethylammonium and 4-aminopirydine, inhibitors of voltage-gated and calciumactivated potassium channels, prevented a NaHS-induced initial increase in basal tone and phasic contraction amplitude. Activation of ATP-dependent potassium channels (KATP-channels) by diazoxide prevented in part a NaHS-induced decrease in basal tone and amplitude of spontaneous contractions. Glibenclamide, an inhibitor of KATP-channels, decreased the inhibitory effect of NaHS on amplitude, basal tone and frequency of spontaneous contractions. It was concluded that in rat gastric smooth muscles the excitatory effect of H2S is mediated by the inhibition of voltagegated and calcium-activated potassium channels, while its inhibitory effect involves the activation of KATP-channels.

Effects of levosimendan on cellular metabolic alterations in patients with septic shock: a randomised controlled study

Mitochondrial dysfunction and consequent cellular energetic failure play a key role in the development of sepsis-related organs failure. Levosimendan, by a calcium-sensitizing mechanism increases myocardial contractility while simultaneously exerting vasodilatory properties via activation of ATP-dependent potassium channels (KATP) [1].

Hydrogen sulfide induces hyperpolarization and decreases the exocytosis of secretory granules of rat GH3 pituitary tumor cells

The aim of the present study was to evaluate the effects of hydrogen sulfide (H2S) on the membrane potential, action potential discharge and exocytosis of secretory granules in neurosecretory pituitary tumor cells (GH3). The H2S donor – sodium hydrosulfide (NaHS) induced membrane hyperpolarization, followed by truncation of spontaneous electrical activity and decrease of the membrane resistance. The NaHS effect was dose-dependent with an EC50 of 152 μM (equals effective H2S of 16–19 μM). NaHS effects were not altered after inhibition of maxi conductance calcium-activated potassium (BK) channels by tetraethylammonium or paxilline, but were significantly reduced after inhibition or activation of ATP-dependent potassium channels (KATP) by glibenclamide or by diazoxide, respectively. In whole-cell recordings NaHS increased the amplitude of KATP currents, induced by hyperpolarizing pulses and subsequent application of glibenclamide decreased currents to control levels. Using the fluorescent dye FM 1–43 exocytosis of secretory granules was analyzed in basal and stimulated conditions (high K+ external solution). Prior application of NaHS decreased the fluorescence of the cell membrane in both conditions which links with activation of KATP currents (basal secretion) and activation of KATP currents and BK-currents (stimulated exocytosis). We suggest that H2S induces hyperpolarization of GH3 cells by activation of KATP channels which results in a truncation of spontaneous action potentials and a decrease of hormone release.

Effect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart.

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.

A journey from benzanilides to dithiobenzanilides: Synthesis of selective spasmolytic compounds

A series of dithiobenzanilide derivatives was synthesized and each compound was evaluated for its ability to reduce KCl-induced contractions of smooth muscle preparations of the guinea pig. Starting from a recent publication describing benzanilide derivatives as antispasmodic agents, structure-activity guided synthesis was performed to obtain compounds with improved spasmolytic activity. First, compounds with two amide bonds were designed and second, both amide oxygens were replaced by two sp² sulfur atoms resulting in dithiobenzanilide derivatives. The most potent antispasmodic dithiobenzanilide 19 showed improved activity with an IC₅₀ value of 0.4 μM. Moreover, the study also demonstrated that these active compounds were able to antagonize the effect of spasmogens like acetylcholine and phenylephrine and that the activity is not mediated by activation of ATP-dependent potassium channels (K(ATP)-channels) or inhibition of endothelial nitric oxide synthase (eNOS).

Artemisia herba-alba Asso relaxes the rat aorta through activation of NO/cGMP pathway and KATP channels

Artemisia herba-alba Asso (Compositae) is used in oriental Morocco to treat diabetes and arterial hypertension. The present work evaluated the vasorelaxant effect of Artemisia herba-alba aqueous extract (AHAE) in isolated rat aorta and the mechanism underlying this effect. In endothelium-containing aorta preparations, AHAE (10(-3), 10(-2), 10(-1), 1 and 2 mg/mL) relaxed the contraction elicited by noradrenaline in a concentration-dependent manner. This effect is dependent upon integrity of the vascular endothelium as it was fully abolished in endothelium-denuded preparations. The vasorelaxant effect of AHAE (2 mg/mL) was also inhibited by N(G)-nitro-L-arginine methyl-ester (100 microM), methylene blue (10 microM) or 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (50 microM) but not by 10 microM atropine. This effect remained unchanged by tetraethylammonium (5 mM) or indomethacin (10 microM) whereas it was significantly attenuated by glibenclamide (10 microM). These results suggest that AHAE produces an endothelium-dependent relaxation of the isolated rat aorta, an effect that seems mainly mediated through stimulation of the endothelial nitric oxide synthase by mechanisms other than activation of muscarinic receptors. Activation of ATP-dependent potassium channels partly contributes in the mediation of AHAE-induced endothelium-dependent relaxation.

Yohimbine relaxes the human corpus cavernosum through a non-adrenergic mechanism involving the activation of K+ATP-dependent channels

The mechanism by which yohimbine relaxes the human corpus cavernosum remains unclear. Using the human corpus cavernosum strips immersed in isometric baths containing Krebs-Henseleit solution, this study investigates the effect of yohimbine on the relaxation of the human corpus cavernosum through nitrergic pathways involving the activation of ATP-dependent potassium channels (K(ATP)). The maximal relaxation induced by yohimbine in the human corpus cavernosum strips pre-contracted with phenylephrine was 100+/-0% and only 30.5+/-5.0% when they were pre-contracted with 60-mM potassium (K(+)) solution. The maximal relaxation induced by yohimbine in phenylephrine pre-contracted tissues was significantly inhibited by tetrodotoxin, 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or 7-nitroindazole (43.6, 36.1 and 42.6%, respectively). Neither the combination charybdotoxin-apamin nor tetraethylammonium altered the response of the human corpora cavernosa strips to yohimbine. Nevertheless, glibenclamide decreased the maximum relaxant response to yohimbine by 29.8% (P<0.05; n=12). The results suggest that yohimbine relaxes the human corpus cavernosum by a non-adrenergic, non-cholinergic mechanism, probably activating the nitrergic-soluble guanylate cyclase (NO-sGc) pathway and K(ATP).

Neuroprotective effect of volatile anesthetic agents: molecular mechanisms

Introduction: Intra-operative cerebral ischemia can be catastrophic, and volatile anesthetic agents have been recognized for their potential neuroprotective properties since the 1960s. In this review, we examine the neuroprotective effects of five volatile anesthetic agents in current or recent clinical use: isoflurane, sevoflurane, desflurane, halothane and enflurane.Methods: A review of publications in the National Library of Medicine and National Institutes of Health database from 1970 to 2007 was conducted.Results: Volatile anesthetic agents have been shown to be neuroprotective in multiple animal works of ischemic brain injury. Short-term neuroprotection (<1 week post-ischemia) in experimental cerebral ischemia has been reported in multiple works, although long-term neuroprotection (≥1 week post-ischemia) remains controversial. Comparison works have not demonstrated superiority of one specific volatile agent over another in experimental models of brain injury. Relatively few human works have examined the protective effects of volatile anesthetic agents and conclusive evidence of a neuroprotective effect has yet to emerge from human works.Conclusion: Proposed mechanisms related to the neuroprotective effect of volatile anesthetic agents include activation of ATP-dependent potassium channels, up-regulation of nitric oxide synthase, reduction of excitotoxic stressors and cerebral metabolic rate, augmentation of peri-ischemic cerebral blood flow and up-regulation of antiapoptotic factors including MAP kinases.

Calcium uptake in rat liver mitochondria accompanied by activation of ATP-dependent potassium channel

The influence of potassium ions on calcium uptake in rat liver mitochondria is studied. It is shown that an increase in K+ and Ca2+ concentrations in the incubation medium leads to a decrease in calcium uptake in mitochondria together with a simultaneous increase in potassium uptake due to the potential-dependent transport of K+ in the mitochondrial matrix. Both effects are more pronounced in the presence of an ATP-dependent K+-channel (K+(ATP)-channel) opener, diazoxide (Dz). Activation of the K+(ATP)-channel by Dz alters the functional state of mitochondria and leads to an increase in the respiration rate in state 2 and a decrease in the oxygen uptake and the rate of ATP synthesis in state 3. The effect of Dz on oxygen consumption in state 3 is mimicked by valinomycin, but it is opposite to that of the classical protonophore uncoupler CCCP. It is concluded that the potential-dependent uptake of potassium is closely coupled to calcium transport and is an important parameter of energy coupling responsible for complex changes in oxygen consumption and Ca2+-transport properties of mitochondria.

Levosimendan in acute heart failure

Numerous adverse effects and an increased mortality are the reasons why many clinicians are often unsuccessful with the inotropic agents presently in use. New therapeutic agents have been developed in the last few years to assist the clinician in the stabilization, support and treatment of cardiovascular disease.One of the newest groups of inotropic agents is a group of agents, which increase the affinity of myofibrils for calcium and are called calcium sensitizers. Calcium sensitizers are the newest heterogeneous group of inotropic agents. The best known representatives of this group are levosimendan and pimobendan. Positive inotropic effects of levosimendan are achieved by its binding to troponin C and calcium, thereby stabilizing the tropomyosin molecule and prolonging the duration of actin-myosin overlap without a change in the net concentration of intracellular calcium. The vasodilatory effect of levosimendan is reached through activation of ATP-dependent potassium channels. This leads to a decrease in both afterload and preload, increased coronary blood flow and a resultant anti-ischemic effect. Levosimendan is therefore categorized as an anti-ischemic inotropic agent. Furthermore, experiments have confirmed that levosimendan as an opener of KATP – channels in the mitochondria and the sarcolemma of myocites may have an effect on the myocardium preconditioning.

Katecholaminrefraktäre Hypotension - aktuelle Entwicklungen

Vasoplegia as catecholamine resistent hypotension occurs in severe hemorrhagic or septic shock and post cardiopulmonary bypass. The entire rational behind this phenomenon is still unclear. An ATP-shortage in the vascular musculature, disregulation of vasopressin release, and the activation of ATP-dependent potassium-channels are discussed. In the last years, attention is drawn towards the activation of ATP-dependent potassium-channels and the possible therapeutic inhibition by glibenclamid. However, inhibition of potassium-channels does not normalize blood pressure under all circumstances. In particular in septic shock other mechanisms have to be involved. Overall, the sometimes desperate clinical situation has led to a large number of case reports und uncontrolled series of retrospectively analysed cases, where vasopressin or methylenblue were discribed as successfully reversing catecholamine resistent hypotension. Nevertheless, in hemorrhagic and septic shock scientific evidence of the clinical effects and the right dose as well as placebo controlled studies comparing the agents and possible combinations of agents are desirable but hardly available yet. In the case of severe hypotension following surgery under cardiopulmonary bypass results of the first randomized and placebo controlled studies describe successful restoration of blood pressure and even a decrease in perioperative mortality. Concerning the side effects, vasopressin and methylenblue, like most vasopressors, can cause gastrointestinal ischemia, but with the small number of patients enrolled so far, further major side effects can not be ruled out. Accordingly, the identification of risk factors for the development of vasoplegia and the prediction of the extent of the response or the rate of non-responders to these treatments are widely unknown. However, although the administration of vasopressin and methylenblue can not be recommended as a standard treatment it provides an additional option in individual cases of life threatening vasoplegia.

Cardioprotective Anesthesia in Patients Undergoing Coronary Surgery: Fact Or fiction?

The use of volatile anesthetics in patients undergoing coronary artery bypass grafting resulted in a shorter length of stay (LOS) in the intensive care unit, shorter LOS in the hospital, and a decreased need for prolonged intensive care. Volatile anesthetics exert cardioprotective effects by anesthetic preconditioning in patients at risk of myocardial ischemia. Sarcolemmal and mitochondrial ATP-dependent potassium channels are the key for anesthetic preconditioning. However, no clinical study has shown that the perioperative use of volatile anesthetics in patients undergoing coronary surgery contributes to a reduced perioperative mortality. For the first time, the study from De Hert and colleagues clearly demonstrates that inhalational anesthesia results in a reduced perioperative cardiac morbidity. In the authors opinion, cardioprotection by activation of ATP-dependent potassium channels will become part of any cardiac revascularization procedure in the future.

A brain-liver circuit regulates glucose homeostasis

Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.

Activation of ATP-dependent potassium channels is a trigger but not a mediator of ischaemic preconditioning in pigs.

1. Activation of ATP-dependent potassium channels (K(ATP)) is involved in ischaemic preconditioning (IP). In isolated buffer-perfused rabbit hearts, activation of mitochondrial K(ATP)--through a generation of free radicals--acted as a trigger rather than a mediator of IP; the isolated buffer-perfused heart preparation, however, favours free radical generation. In contrast, in vivo studies in rats and dogs suggested that activation of K(ATP) acts as a mediator of IP's protection. A detailed analysis on the role of K(ATP) in IP's protection in vivo by varying the time and dose of K(ATP) blocker administration is, however, lacking. 2. In 54 enflurane-anaesthetized pigs, the left anterior descending coronary artery was perfused by an extracorporeal circuit. Infarct size (IS, %, TTC) following 90 min sustained low-flow ischaemia and 120 min reperfusion was 26.6+/-3.5 (s.e.m.) (n=8). IP with one cycle of 10 min ischaemia and 15 min reperfusion reduced IS to 6.5+/-2.1 (n=7, P<0.05). Blockade of K(ATP) with glibenclamide (0.5 mg kg(-1) i.v., 50 microg min(-1) continuous infusion) starting 10 min before or immediately following the preconditioning ischaemia abolished IS reduction by IP (20.7+/-2.7, n=7 and 21.9+/-6.6, n=6, respectively) while having no effect on IS per se (22.2+/-5.2, n=7), supporting a trigger role of K(ATP) in IP. In contrast, starting glibenclamide following the preconditioning ischaemia 10 min prior to the sustained ischaemia did not prevent IS reduction by IP (3.7+/-2.3, n=6), even when its bolus dose was increased to 1.5 mg kg(-1) (26.6+/-3.8 with IP vs 37.5+/-2.9 without IP; n=7 and 6 respectively, P<0.05), thereby refuting a mediator role of K(ATP) in IP. 3. In conclusion, activation of K(ATP) in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP.

Signaling and cellular mechanisms in cardiac protection by ischemic and pharmacological preconditioning.

Ischemic preconditioning (IPC) is a defensive adaptive cellular phenomenon. Brief ischemic stimuli render the heart resistant to subsequent similar stress. Signaling for IPC and pharmacologically induced preconditioning involves several G-protein coupled cell surface receptors, second messengers, specific Ser-Thr-protein kinase-C isoforms, Tyr-kinases, and finally, results in activation of ATP-dependent potassium channels (inward rectifiers) at the sarcolemma and in the mitochondria. In cardiomyocytes these channels regulate cytosolic and mitochondrial Ca2+ levels. K+ influx into mitochondria proves to be a key factor for keeping the mitochondrial permeability transition pore closed. This ensures continuous energy production and prevents cell death by apoptosis or necrosis. Molecular structure, function, and pharmacological properties of the ATP-dependent potassium channels and of the mitochondrial permeability transition pore are discussed. Channel activating agents mimic IPC and also affect reactive oxygen species producing enzymes involved in mitochondrial respiration. Volatile anesthetics, among other drugs, mimic the cardioprotective effects of IPC. Their intracellular signaling and clinical application are briefly discussed.

Activation of ATP-dependent potassium channels is trigger but not mediator of ischemic preconditioning in pigs

Activation of ATP-dependent potassium channels is trigger but not mediator of ischemic preconditioning in pigs

Short-term hibernating myocardium: circulation, function and metabolism in sustained regional myocardial ischemia

During moderate prolonged myocardial ischemia, the myocardium is dysfuctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow, i.e., a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns to control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". "Short-term hibernating" myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. A role for endogenous adenosine in the development of hibernation has been excluded, since neither contractile function, metabolic parameters, nor viability are altered by increased catabolism of endogenous adenosine by infusion of adenosine deaminase. Also activation of ATP-dependent potassium channels is not responsible for "short-term hibernation". "Short-term hibernating" myocardium has, however, reduced calcium responsiveness.