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Critical care medicine 02/2013; 41(2):e15. · 6.37 Impact Factor
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Critical care medicine 01/2013; 41(1):e7-8. · 6.37 Impact Factor
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ABSTRACT: Aim: The present study investigated whether eNOS-activation may be dysregulated in cardiac tissue of patients suffering from type 2 diabetes (T2D). Main methods: We performed immunohistochemical measurements of translocated eNOS-activation as well as eNOS-phosphorylation at Ser1177, Thr495, Ser 635, Ser114 and of the protein kinase B (Akt) in isolated right atrial trabeculae of patients undergoing cardiac bypass or valve surgery with (n=12, 68.1 ± 2.5 years) and without T2D (n=12, 64.7 ± 2.7 years). In addition, we investigated oxidative (8-isoprostane) and nitrosative stress markers (nitrotyrosine) as well as the effect of pharmacological stimulation of angiotensin (AT)-receptors on eNOS-phosphorylation. Key findings: Translocation-dependent eNOS-activation was similar in both groups. The same holds true for eNOS-phosphorylation at Ser114. eNOS-phosphorylation at Ser635 was significantly increased, whereas eNOS-phosphorylation of Ser1177 was significantly decreased in the diabetic group paralleled by a decrease in phosphorylation of Akt and Thr495. These alterations were accompanied by a significant decrease in nitrotyrosine. After application of angiotensin II (10 µM, 2 min.) for investigation of the AT-receptor-dependent eNOS-stimulation, we did not find differences between the increases in eNOS-Ser1177-phosphorylation in the non-diabetic (+39.7% ± 23.5%) and in the diabetic group (32.22% ± 11.45%). A simultaneous increase in Akt-phosphorylation could not be observed. Significance: The present study indicates that T2D goes along with a decrease in eNOS-phosphorylation at Ser1177 under basal conditions in cardiac tissue. Whether this may be attributed to the insulin resistance of cardiac muscle has to be further investigated. Receptor-stimulated eNOS-activation still works at least for angiotensin II-dependent eNOS-activation.
Journal of Applied Physiology 12/2012; · 3.75 Impact Factor
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Resuscitation 09/2012; · 3.60 Impact Factor
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ABSTRACT: AIM OF THE STUDY: It has recently been suggested that acute kidney injury (AKI) may strongly be influenced by post-resuscitation disease and cardiogenic shock (CS), and may not just be a consequence of cardiac arrest and time without spontaneous circulation. AKI also has been suggested as a strong independent predictor of in-hospital mortality. Therefore the present study aimed at investigating the effect of fluid management on the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated by mild therapeutic hypothermia. METHODS: Fluid therapy and the incidence of acute kidney injury (AKI) was retrospectively reviewed in 51 patients with cardiogenic shock after cardiac arrest comparing patients with and without hemodynamic (PPV, SVV) and volumetric (ELWI, GEDI) monitoring. RESULTS: There was no significant difference in baseline or cardiac arrest characteristics between hemodynamic monitored patients and conventional monitored patients. 28 patients were monitored by standard monitoring, in 23 patients monitoring was complemented by a PICCO system. In the first 24h of treatment the total amount of fluid was significantly higher in patients under PICCO monitoring compared to conventional monitoring (4375±1285ml vs. 5449±1438ml, p=0.007). This was associated with a significant reduction in the incidence of AKI (RIFLE 'I'/'F': PICCO-group: 1 (4.3%) vs. conventional group 8 (28.6%), p=0.03). CONCLUSION: The presented data suggest that volume therapy guided by volumetric (ELWI, GEDI) and arterial waveform derived variables (PPV, SVV) can reduce the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated with mild therapeutic hypothermia.
Resuscitation 06/2012; · 3.60 Impact Factor
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ABSTRACT: The fast cycling of calcium between internal stores and the myofilaments with rapid diffusion down steep concentration gradients provides the cellular basis for cardiac contraction and relaxation. In heart failure, the intracellular Ca(2) (+) dynamics are impaired showing reduced systolic peak Ca(2) (+), elevated diastolic Ca(2) (+) levels, and prolonged diastolic Ca(2) (+) decay. The recognition that defects in the function of Ca(2) (+) handling proteins are central to the pathogenesis of heart failure has attracted attention to these proteins as potential targets for therapy. Besides pharmacologic interventions including digitalis, ranolazine, levosimendan and others, cardiac gene therapy holds great promise and the recent clinical studies have proven the feasibility of this therapeutic approach. In this review, the rationale underlying modern therapies that modulate intracellular Ca(2) (+) handling for the treatment of human heart failure are presented and discussed.
Wiener Medizinische Wochenschrift 06/2012; 162(13-14):297-301.
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Hannes Reuter,
Katharina Seuthe,
Yüksel Korkmaz,
Sabine Grönke,
Dieter Paul Hoyer,
Dennis Rottlaender,
Carsten Zobel,
Klaus Addicks,
Johanna Hoyer,
Peter Grimminger,
Jan Brabender,
Thomas M Wilkie,
Erland Erdmann
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ABSTRACT: AIMS/HYPOTHESIS: Pathological cardiac hypertrophy is an early phenotype in both types 1 and 2 diabetes. The primary stimulus for hypertrophic growth in diabetes is yet unknown and may involve neurohumoral stimulation of Gq-coupled receptors as well as direct glucose-dependent mechanisms. To discriminate between these hypertrophic stimuli we analyzed hypertrophic signalling pathways in wildtype and Gα(11)-knockout mice. METHODS: Experimental diabetes was induced in wildtype and knockout mice by intraperitoneal injection of streptozotocin. 8weeks after induction of diabetes myocardial function and structure was assessed by echocardiography before sacrifice. To identify prohypertrophic signalling pathways expression and translocation of protein kinase C isoforms α, β(II), δ, ε and ζ were analyzed by immunohistochemical staining and immunoblot analysis after tissue fractionation. Changes in calcineurin signalling were identified by immunoblot analysis and functional assays. Expression levels of transcription factors GATA4 and NF-κB were quantified by real-time RT-PCR. RESULTS: Diabetic wildtype mice developed myocardial hypertrophy with preserved cardiac function. Calcineurin signalling was not different between the two groups. However, diabetic wildtype mice showed increased protein levels of PKC-α and PKC-ζ, translocation of PKC-α, -δ and -ε to cellular membranes and higher levels of NF-κB expression. In contrast, diabetic Gα(11)-knockout mice showed no altered phenotype and no changes in NF-κB or PKC expression, although translocation of PKC-ε occurred as in wildtypes. CONCLUSIONS: Gα(11) is essential for the development of cardiac hypertrophy in type 1-diabetes. Stimulation of hypertrophic signalling through PKC-α, PKC-δ, PKC-ζ, and NF-κB appears to be receptor-dependent, whereas PKC-ε is activated by hyperglycemia, independent of Gα(11).
International journal of cardiology 05/2012; · 7.08 Impact Factor
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ABSTRACT: Neurohumoral stimulation of Gq-coupled receptors has been proposed as a central mechanism in the pathogenesis of diabetic
heart disease. The resulting contractile dysfunction is closely related to abnormal intracellular Ca2+ handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine
the role of Gq-protein signaling via Gα11 and Gαq in diabetes for the induction of functional and structural changes in the Ca2+ release complex of the SR. An experimental type 1-diabetes was induced in wild type, Gα11 knockout, and Gα11/q-knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR
Ca2+ leak was tested in vitro based on a 45Ca2+ assay and protein densities as well as gene expression of ryanodine receptor (RyR2), FKBP12.6, sorcin, and annexin A7 were
analyzed by immunoblot and RT-PCR. In wild type animals 8weeks of diabetes resulted in cardiac hypertrophy and SR Ca2+ leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In
Gα11- and Gα11/q-knockout animals, however, SR Ca2+ release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently
analyzed were also unaltered in Gα11-knockout mice. Gα11/q-knockout animals even showed increased expression of sorcin and annexin A7. Thus, based on the present study we suggest a
signaling pathway via the Gq-proteins, Gα11 and Gαq, that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein
expression of FKBP12.6, annexin A7, and sorcin.
KeywordsRyanodine receptor-Type 1-diabetes-Knockout mice-Sorcin-Annexin A7
Molecular and Cellular Biochemistry 04/2012; 341(1):235-244. · 2.06 Impact Factor
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ABSTRACT: Mortality in patients with cardiogenic shock after out-of-hospital cardiac arrest remains high despite advances in resuscitation and early revascularization strategies. Recent studies suggest a reduced mortality in survivors of cardiac arrest subjected to mild therapeutic hypothermia, but the underlying mechanisms are not yet clear. Because positive hemodynamic effects of mild therapeutic hypothermia have been suggested, we aimed at testing the hypothesis that patients in cardiogenic shock might benefit from mild therapeutic hypothermia.
Hemodynamic effects of mild therapeutic hypothermia in 20 consecutive patients admitted in cardiogenic shock after successful resuscitation from out-of-hospital cardiac arrest were investigated. A historic normothermic control group was matched (one-to-one) by means of a propensity score. Patients were cooled to 33°C for 24 hrs using an endovascular cooling device and hemodynamic variables were continuously recorded by means of pulse contour analysis. Cardiac performance was determined by echocardiography.
Mild therapeutic hypothermia induced a significant decrease in heart rate from 74 to 64 beats per minute. Despite the reduction in heart rate, cardiac index remained unchanged under mild therapeutic hypothermia likely due to an increase in ejection fraction from 43 ± 4% to 55 ± 4%. Mean arterial pressure increased rapidly from 75 ± 2 mm Hg to 84 ± 3 mm Hg (p = .001) upon induction of hypothermia paralleled by an initial increase in systemic vascular resistance. Accordingly, patients with mild therapeutic hypothermia required lower cumulative doses of vasopressors and inotropes.
We conclude that in cardiogenic shock mild therapeutic hypothermia provides circulatory support and an increase in systemic vascular resistance that leads to reduced vasopressor use and may result in lower oxygen consumption. These findings suggest that mild therapeutic hypothermia could be a therapeutic option in hemodynamically unstable patients independent of cardiac arrest and further randomized clinical studies are needed.
Critical care medicine 04/2012; 40(6):1715-23. · 6.37 Impact Factor
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ABSTRACT: There are no reliable data on mortality and morbidity of adult patients in modern university-based cardiac intensive care units. Therefore, the present study was aimed to provide complete data in respect to mortality and morbidity of all patients admitted between 1 January 2008 and 31 December 2009 to the newly opened cardiac intensive care unit of the Heart Centre of the Cologne University Hospital.
All patients admitted to the 6-bed intensive care unit of the Heart Centre of the University of Cologne between January 1 2008 and December 31 2009 were included in this study.
A total of 684 patients were investigated. The majority of patients (71.1%) were male. The overall in-hospital mortality was 32.5%. The most frequent diagnosis was acute coronary syndrome (43.6%). Coronary angiography was performed in 45.5% of all patients. Cardiopulmonary resuscitation was the reason for admission in 30.8%, the in-hospital mortality of those patients (46.0%) was much higher compared to the overall mortality.
Our data demonstrate that despite state-of-the-art university-based intensive care medicine with modern equipment the mortality remains high. These findings will help in calculating the resources required to meet the increasing demand for intensive care medicine.
Clinical Research in Cardiology 02/2012; 101(7):521-4. · 2.95 Impact Factor
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Carina Lammers,
Theresa Dartsch,
Mathias C Brandt,
Dennis Rottländer,
Marcel Halbach,
Gabriel Peinkofer,
Simon Ockenpoehler,
Marco Weiergraeber,
Toni Schneider, Hannes Reuter,
Jochen Müller-Ehmsen,
Jürgen Hescheler,
Uta C Hoppe,
Carsten Zobel
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ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. The Renin-Angiotensin-Aldosterone-System plays a major role for the atrial structural and electrical remodelling. Recently elevated aldosterone levels have been suggested to increase the risk for the development of AF.
Rats were treated with aldosterone by means of an osmotic minipump (0.5μg/h) over a period of 4 weeks. AF was induced by transesophageal burst pacing. Action potentials (AP) were recorded from left atrial preparations with microelectrodes. Atrial collagen was quantified by histological studies.
Aldosterone treatment resulted in hypertrophy as indicated by an increased ratio of heart weight/tibia length and doubled the time until the AF converted spontaneously into sinus rhythm (85.8±13.4 s vs. 38.3±6.9 s, p<0.01). This was associated with a significant shortening of the AP (APD90 26.2±1.1 vs. 31.2±1.9, p<0.05) and an increased protein expression of Kir2.1 and Kv1.5. Atrial collagen deposition was significantly greater in aldosterone-treated rats. The alterations could be prevented by additional application spironolactone.
The results of the present study suggest that in addition to the structural remodelling aldosterone also promotes AF by altering repolarising potassium currents leading to action potential shortening.
Cellular Physiology and Biochemistry 01/2012; 29(5-6):833-40. · 2.86 Impact Factor
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ABSTRACT: BACKGROUND: Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. METHODS AND RESULTS: Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (I(to)), Kv1.5 (I(Kur)), Kir2.1 and Kir2.3 (I(K1)) and of Ca(v)1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. CONCLUSIONS: Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.
International journal of cardiology 07/2011; · 7.08 Impact Factor
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Resuscitation 02/2011; 82(2):238-9. · 3.60 Impact Factor
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Clinical Research in Cardiology 12/2010; 100(4):379-82. · 2.95 Impact Factor
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ABSTRACT: Neurohumoral stimulation of Gq-coupled receptors has been proposed as a central mechanism in the pathogenesis of diabetic heart disease. The resulting contractile dysfunction is closely related to abnormal intracellular Ca(2+) handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine the role of G(q)-protein signaling via G(alpha)(11) and G(alpha)(q) in diabetes for the induction of functional and structural changes in the Ca(2+) release complex of the SR. An experimental type 1-diabetes was induced in wild type, G(alpha)(11) knockout, and G(alpha)(11/q)-knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR Ca(2+) leak was tested in vitro based on a (45)Ca(2+) assay and protein densities as well as gene expression of ryanodine receptor (RyR2), FKBP12.6, sorcin, and annexin A7 were analyzed by immunoblot and RT-PCR. In wild type animals 8 weeks of diabetes resulted in cardiac hypertrophy and SR Ca(2+) leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In G(alpha)(11)- and G(alpha)(11/q)-knockout animals, however, SR Ca(2+) release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently analyzed were also unaltered in G(alpha)(11)-knockout mice. G(alpha)(11/q)-knockout animals even showed increased expression of sorcin and annexin A7. Thus, based on the present study we suggest a signaling pathway via the G(q)-proteins, G(alpha)(11) and G(alpha)(q), that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein expression of FKBP12.6, annexin A7, and sorcin.
Molecular and Cellular Biochemistry 04/2010; 341(1-2):235-44. · 2.06 Impact Factor
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ABSTRACT: Diabetes mellitus counts as a major risk factor for developing atherosclerosis. The activation of protein kinase C (PKC) is commonly known to take a pivotal part in the pathogenesis of atherosclerosis, though the influence of specific PKC isozymes remains unclear. There is evidence from large clinical trials suggesting excessive neurohumoral stimulation, amongst other pathways leading to PKC activation, as a central mechanism in the pathogenesis of diabetic heart disease. The present study was therefore designed to determine the role of Gq-protein signalling via Gα11 in diabetes for the expression of PKC isozymes in the coronary vessels.
The role of Gα11 in diabetes was examined in knockout mice with global deletion of Gα11 compared to wildtype controls. An experimental type 1-diabetes was induced in both groups by injection of streptozotocin. Expression and localization of the PKC isozymes α, βII, δ, ε, and ζ was examined by quantitative immunohistochemistry.
8 weeks after induction of diabetes a diminished expression of PKC ε was observed in wildtype animals. This alteration was not seen in Gα11 knockout animals, however, these mice showed a diminished expression of PKCζ. Direct comparison of wildtype and knockout control animals revealed a diminished expression of PKC δ and ε in Gα11 knockout animals.
The present study shows that expression of the nPKCs δ and ε in coronary vessels is under control of the g-protein Gα11. The reduced expression of PKC ζ that we observed in coronary arteries from Gα11-knockout mice compared to wildtype controls upon induction of diabetes could reduce apoptosis and promote plaque stability. These findings suggest a mechanism that may in part underlie the therapeutic benefit of RAS inhibition on cardiovascular endpoints in diabetic patients.
Cardiovascular Diabetology 01/2010; 9:93. · 3.35 Impact Factor
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Hannes Reuter,
Sabine Grönke,
Christian Adam,
Maida Ribati,
Jan Brabender,
Carsten Zobel,
Konrad F Frank,
Jens Wippermann,
Robert H G Schwinger,
Klara Brixius,
Jochen Müller-Ehmsen
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ABSTRACT: Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca(2+) regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca(2+) transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca(2+) handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca(2+) handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca(2+) was significantly prolonged, but relaxation of the Ca(2+) transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca(2+) release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca(2+) release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca(2+) release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.
Molecular and Cellular Biochemistry 02/2008; 308(1-2):141-9. · 2.06 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. In recent studies, a decrease in the development or recurrence of AF was found in hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking agents. Hypertension is related to an increased wall tension in the atria, resulting in increased stretch of the individual myocyte, which is one of the major stimuli for the remodeling process. In the present study, we used a model of cultured atrial neonatal rat cardiomyocytes under conditions of stretch to provide insight into the mechanisms of the preventive effect of the angiotensin receptor-blocking agent losartan against AF on a molecular level. Stretch significantly increased protein-to-DNA ratio and atrial natriuretic factor mRNA expression, indicating hypertrophy. Expression of genes encoding for the inward rectifier K(+) current (I(K1)), Kir 2.1, and Kir 2.3, as well as the gene encoding for the ultrarapid delayed rectifier K(+) current (I(Kur)), Kv 1.5, was significantly increased. In contrast, mRNA expression of Kv 4.2 was significantly reduced in stretched myocytes. Alterations of gene expression correlated with the corresponding current densities: I(K1) and I(Kur) densities were significantly increased in stretched myocytes, whereas transient outward K(+) current (I(to)) density was reduced. These alterations resulted in a significant abbreviation of the action potential duration. Losartan (1 microM) prevented stretch-induced increases in the protein-to-DNA ratio and atrial natriuretic peptide mRNA expression in stretched myocytes. Concomitantly, losartan attenuated stretch-induced alterations in I(K1), I(Kur), and I(to) density and gene expression. This prevented the stretch-induced abbreviation of action potential duration. Prevention of stretch-induced electrical remodeling might contribute to the clinical effects of losartan against AF.
AJP Heart and Circulatory Physiology 07/2007; 292(6):H2898-905. · 3.71 Impact Factor
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ABSTRACT: The Na+/Ca2+ exchanger (NCX) is involved in embryonic heart development and function demonstrated by the abnormal myofibrillar organization, defects in heartbeat, and early embryonic death of NCX-null embryos. It was therefore the aim of our study to identify key functional regulators of the embryonic NCX.
NCX current (I(NCX)) density was measured as the Ni2+ (5 mM)-sensitive current applying the whole-cell patch-clamp technique in early (EDS, E10.5V) and late developmental stage (LDS, E16.5V) mouse ventricular cardiomyocytes.
Compared to LDS, cardiomyocytes derived from EDS showed a significantly higher basal I(NCX) density for the I(NCX) forward (-120 mV: -4.1+/-1 pA/pF, n=15 versus -1.7+/-0.4, n=11, p<0.05) and reverse modes (+60 mV: 4.0+/-0.9 pA/pF, n=15 versus 1.8+/-0.4, n=11, p<0.05). There was 2-3-fold elevation of forward and reverse current in LDS on application of ATP-gamma-S (2 mM) together with forskolin (1 microM) as well as intracellular application of the catalytic subunit of cAMP-dependent protein kinase (cPKA, 200 U/mL), cAMP (200 microM), phorbol 12-myristate-13-acetate (PMA), a direct activator of protein kinase C (PKC), and 8-Br-cGMP, a membrane permeable analog of cGMP. The specific PKC inhibitor Ro 31-8220 significantly reduced I(NCX) by 70%. Co-application of 20 microM PKA inhibitor Fragment 14-22 (PKI), a specific inhibitor of PKA, and cAMP significantly reduced the exchanger activity by approx 60%. Despite these obvious effects in LDS we could not detect a significant impact of these compounds on I(NCX) in EDS-derived cardiomyocytes. Application of the alkaline phosphatase to test for constitutive phosphorylation of NCX did not affect I(NCX) density in LDS but led to an approx 80% reduction of I(NCX) in EDS.
In EDS cardiomyocytes I(NCX) density is upregulated, at least in part by the high phosphorylation of the exchanger protein. At LDS, embryonic cardiomyocytes showed a strong increase of I(NCX) density upon stimulation by PKC- and PKA-dependent signalling pathways.
Cardiovascular Research 07/2007; 75(1):99-108. · 6.06 Impact Factor
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ABSTRACT: Due to its high functional expression, INCX may serve as an important mechanism to ensure intracellular Ca2+ homeostasis, especially during the early embryonic stage. At the fetal stage INCX density is significantly decreased but underlies regulatory processes, that is, regulation by Na+.
Annals of the New York Academy of Sciences 04/2007; 1099(1):175 - 182. · 3.15 Impact Factor
