Cellular Mechanisms Responsible for the Inotropic Action of Insulin on Failing Human Myocardium

Hsu, Chih-Hsueng; Wei, Jeng; Chen, Yao‐Chang; Yang, Shih-Ping; Tsai, Chien-Song; Lin, Cheng‐I

doi:10.1016/j.healun.2006.05.010

Cited by 25 publications

(14 citation statements)

References 41 publications

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“…This effect is mediated either directly, through the activation of PI-3-kinase [26, 27], or indirectly, through increased activation of the Na + –H + exchanger, which transports Na + into the cell in exchange for H + . By enhancing the activity of the Na + –H + exchanger, thereby increasing the intracellular sodium concentration, the reverse mode of the Na + –Ca 2+ exchanger is activated, which will extrude Na from the cell in exchange for calcium [26, 28]. Insulin also promotes a positive inotropic effect through enhancing the SR Ca 2+ uptake of calcium into the sarcoplasmic reticulum [26–28].…”

Section: Discussionmentioning

confidence: 99%

“…By enhancing the activity of the Na + –H + exchanger, thereby increasing the intracellular sodium concentration, the reverse mode of the Na + –Ca 2+ exchanger is activated, which will extrude Na from the cell in exchange for calcium [26, 28]. Insulin also promotes a positive inotropic effect through enhancing the SR Ca 2+ uptake of calcium into the sarcoplasmic reticulum [26–28]. These effects may be significant in combating the myocardial depressive effect of the various cytokines that are active in sepsis.…”

Section: Discussionmentioning

confidence: 99%

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Use of Insulin to Decrease Septic Shock-Induced Myocardial Depression in a Porcine Model

et al. 2013

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Insulin is known to attenuate septic shock-induced myocardial depression. Possible mechanisms include an anti-inflammatory or inotropic effect of insulin. The objective of this study was to determine whether the mechanism of action of insulin in attenuating septic shock-induced myocardial depression is through an immunomodulatory effect. Fourteen pigs were assigned to one of two groups. Both groups received a 4-h infusion of lipopolysaccharide endotoxin from Escherichia coli 0111:B4. Group 2 additionally received insulin at 1.5 U/kg/h with infusions of D50 normal saline and KCl to maintain normal serum glucose and potassium levels. Cardiac function was measured with shortening fraction using transthoracic echocardiogram. Plasma TNF-α, IL-1β, and IL-6 levels were obtained every 30 min. Postmortem cytokine analysis and histomorphology were performed on the heart tissue. Although insulin attenuated septic shock-induced myocardial depression, this was not due to an anti-inflammatory effect and, therefore, likely resulted from an inotropic effect of insulin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Use of Insulin to Decrease Septic Shock-Induced Myocardial Depression in a Porcine Model

et al. 2013

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“…Hsu et al (10) reported that insulin increased isometric twitch force of explanted muscle strips from failing human hearts by ϳ45%. The effect could be partially prevented by blockade of the sarcoplasmic reticulum Ca 2ϩ -ATPase, inhibition of Na ϩ -H ϩ exchange, or inhibition of Na ϩ -Ca 2ϩ exchange, although L-type Ca 2ϩ currents in isolated myocytes were also shown to be increased by insulin.…”

Section: Discussionmentioning

confidence: 99%

“…The sarcolemmal Na ϩ /Ca 2ϩ exchanger (NCX) 2 has been shown to be an insulin-sensitive target; NCX protein and mRNA expression levels are significantly depressed in some diabetic animal models (7,8), and NCX activity, but not mRNA, was decreased in streptozotocin-treated neonatal rats (9). NCX regulation by insulin has also been proposed as one of the underlying mechanisms responsible for the positive inotropic effect of insulin on the failing myocardium (10,11). Because NCX is the main mechanism for removing Ca 2ϩ from the cell, accounting for up to 30% of the total systolic Ca 2ϩ removal in large animals, a significant reduction in exchanger activity could increase intracellular Ca 2ϩ and may contribute to diabetic cardiomyopathy as a result of altered diastolic Ca 2ϩ removal (12).…”

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confidence: 99%

Insulin Effects on Cardiac Na+/Ca2+ Exchanger Activity

Villa‐Abrille

Sidor

O’Rourke

2008

Journal of Biological Chemistry

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Insulin can alter myocardial contractility, in part through an effect on the cardiac sarcolemmal Na ؉ /Ca 2؉ exchanger (NCX), but little is known about its mechanism of action. The large cytoplasmic domain (f-loop) of NCX is required for regulation by various intracellular factors, and we have shown previously that residues 562-679 are determinants of NCX inhibition by exchanger inhibitory peptide (XIP). Here we show that the same f-loop deletion eliminates the enhancement of NCX current by insulin, and we examine the signal pathways involved in the insulin response. NCX current (I NCX ) was measured in freshly isolated or cultured (up to 48 h) adult guinea pig myocytes and in myocytes expressing canine NCX1.1 with the 562-679 f-loop deletion (NCX-(⌬562-679)) via adenoviral gene transfer. I NCX was recorded by whole-cell patch clamp as the Ni 2؉ -sensitive current at 37°C with intracellular Ca 2؉ buffered. Insulin (1 M) increased I NCX (at ؉80 mV) by 110 and 83% in fresh and cultured myocytes, respectively, whereas in myocytes expressing NCX-(⌬562-679) the response was eliminated (with 100 M XIP included to suppress any native guinea pig I NCX ). The insulin effect on I NCX was not inhibited by wortmannin, a nitricoxide synthase inhibitor, or disruption of caveolae but was blocked by chelerythrine, implicating protein kinase C, but not phosphatidylinositol-3-kinase, in the mechanism. The insulin effect was also not additive with phosphatidylinositol-4,5-bisphosphate-induced activation of I NCX . The finding that the 562-670 f-loop domain is implicated in both XIP and receptormediated modulation of NCX highlights its important role in acute physiological or pathophysiological regulation of Ca 2؉ balance in the heart.Insulin is an essential hormone for the control of blood glucose concentration. In the heart, insulin affects many physiological and pathological functions, including energy metabolism, contractility (1, 2), ion transport (3), cardiac protection (4), hypertrophy (5), and cardiomyopathy in diabetes (6). The sarcolemmal Na ϩ /Ca 2ϩ exchanger (NCX) 2 has been shown to be an insulin-sensitive target; NCX protein and mRNA expression levels are significantly depressed in some diabetic animal models (7,8), and NCX activity, but not mRNA, was decreased in streptozotocin-treated neonatal rats (9). NCX regulation by insulin has also been proposed as one of the underlying mechanisms responsible for the positive inotropic effect of insulin on the failing myocardium (10, 11). Because NCX is the main mechanism for removing Ca 2ϩ from the cell, accounting for up to 30% of the total systolic Ca 2ϩ removal in large animals, a significant reduction in exchanger activity could increase intracellular Ca 2ϩ and may contribute to diabetic cardiomyopathy as a result of altered diastolic Ca 2ϩ removal (12). The pleiotropic actions of insulin are mediated by a cascade of parallel signaling pathways within the cell. The binding of insulin to its receptor results in the activation of its intrinsic protein tyrosine kinase activi...

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“…In an experiment on explanted human myocardium, von Lewinski et al demonstrated the positive inotropic effect of insulin through calcium‐dependent pathways as well as PI3K pathways . Moreover, Hsu et al demonstrated with human myocardial cells that this inotropic property of insulin was dose dependent, with better responses observed after the use of higher doses of insulin; in addition, this effect was rapid (ie, as fast as 5 minutes after the infusion) and was sustained throughout the duration of insulin treatment . The best clinical translation of this finding was demonstrated by Yuan et al in their case series of 5 patients with severe cardiogenic shock secondary to CCB overdoses.…”

Section: Management Approachmentioning

confidence: 99%

Management of calcium channel blocker overdoses

Shenoy

Lankala

Adigopula

2014

Journal of Hospital Medicine

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Calcium channel blockers (CCBs) are some of the most commonly used medications in clinical practice to treat hypertension, angina, cardiac arrhythmias, and some cases of heart failure. Recent data show that CCBs are the most common of the cardiovascular medications noted in intentional or unintentional overdoses.1 Novel treatment approaches in the form of glucagon, high‐dose insulin therapy, and intravenous lipid emulsion therapies have been tried and have been successful. However, the evidence for these are limited to case reports and case series. We take this opportunity to review the various treatment options in the management of CCB overdoses with a special focus on high‐dose insulin therapy as the emerging choice for initial therapy in severe overdoses. Journal of Hospital Medicine 2014;9:663–668. © 2014 Society of Hospital Medicine

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Cellular Mechanisms Responsible for the Inotropic Action of Insulin on Failing Human Myocardium

Cited by 25 publications

References 41 publications

Use of Insulin to Decrease Septic Shock-Induced Myocardial Depression in a Porcine Model

Use of Insulin to Decrease Septic Shock-Induced Myocardial Depression in a Porcine Model

Insulin Effects on Cardiac Na+/Ca2+ Exchanger Activity

Management of calcium channel blocker overdoses

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