C Krüger

St. Josefs Hospital, Клоппенбург, Lower Saxony, Germany

Are you C Krüger?

Claim your profile

Publications (17)97.46 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to assess cognitive impairment in patients with chronic heart failure (CHF) and its associations with depressive symptoms and somatic indicators of illness severity, which is a matter of controversy. Fifty-five patients with CHF (mean age 55.3 ± 7.8 years; 80% male; New York Heart Association functional class I-III) underwent assessment with an expanded neuropsychological test battery (eg, memory, complex attention, mental flexibility, psychomotor speed) to evaluate objective and subjective cognitive impairment. Depressive symptoms were assessed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) and a self-report inventory (Hospital Anxiety and Depression Scale [HADS]). A comprehensive clinical dataset, including left ventricular ejection fraction, peak oxygen uptake, and a 6-minute walk test, was obtained for all patients. Neuropsychological functioning revealed impairment in 56% of patients in at least one measure of our neuropsychological test battery. However, the Mini Mental State Examination (MMSE) could only detect cognitive impairment in 1.8% of all patients, 24% had HADS scores indicating depressive symptoms, and 11.1% met SCID criteria for a depressive disorder. No significant association was found between depressive symptoms and cognitive impairment. Left ventricular ejection fraction was related to subjective cognitive impairment, and peak oxygen uptake was related to objective cognitive impairment. Cognitive functioning was substantially reduced in patients with CHF and should therefore be diagnosed and treated in routine clinical practice. Caution is advised when the MMSE is used to identify cognitive impairment in patients with CHF.
    International Journal of General Medicine 01/2011; 4:879-87.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prognostic role of asymptomatic nonsustained ventricular tachycardia (NSVT) and programmed ventricular stimulation (PVS) in patients with idiopathic dilated cardiomyopathy (IDC) remains controversial. The prognostic significance of ventricular arrhythmias, ejection fraction, NYHA class, atrial fibrillation and age for overall and sudden death mortality was prospectively studied in 157 patients with IDC (group 1) free of documented sustained ventricular arrhythmia and syncope. In 99 patients with asymptomatic NSVT (group 2), PVS with 2 - 3 extrastimuli was performed. Non-inducible patients were discharged without specific antiarrhythmic therapy, whereas those with inducible monomorphic ventricular tachycardia were implanted with an ICD. In group 1, 48% of patients had NSVT. Overall and sudden death mortality were significantly higher in patients with NSVT (34.2 vs. 9.8%, p = 0.0001 and 15.8 vs. 3.7%, p = 0.0037; follow-up 22 +/- 14 months). Multivariate analysis revealed that NSVT independently predicts both overall and sudden death mortality (p = 0.0021 and.0221, respectively; adjusted for EF, NYHA class and age). In group 2, inducibility of sustained ventricular tachyarrhythmia was 7%, but sustained monomorphic VT occurred in 3% only. Two of 7 inducible patients experienced arrhythmic events during a follow-up of 25 +/- 21 months (positive predictive value 29%). Overall and sudden death mortality were 29% and 0% in the inducible group vs. 17 and 4% in the non-inducible group. Both overall and sudden death mortality were significantly lower in non-inducible patients from group 2 as compared to patients from group 1 with NSVT (p = 0.0043 and 0.0048), most likely due to a more common use of betablockers and a higher EF in the former group (p < 0.001, respectively). In patients with IDC, NSVT independently predicts both overall and sudden death mortality. Due to a low inducibility rate and a poor positive predictive value, PVS seems inappropriate for further arrhythmia risk assessment. However, in spite of documented NSVT, the incidence of SCD in patients on optimized medical treatment including betablockers seems to be very low, questioning the need for specific arrhythmia risk stratification.
    Archiv für Kreislaufforschung 07/2003; 98(4):259-66. · 5.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This prospective study evaluated whether heart rate variability (HRV) assessed from Holter ECG has prognostic value in addition to established parameters in patients with congestive heart failure (CHF). The study included 222 patients with CHF due to dilated or ischemic cardiomyopathy (left ventricular ejection fraction LVEF 21+/-1%; mean+/-SEM). During a mean follow-up of 15+/-1 months, 38 (17%) patients died and 45 (20%) were hospitalized due to worsening of CHF. The HRV parameter SDNN (standard deviation of all intervals between normal beats) was significantly lower in non-surviving or hospitalized than in event-free patients (118+/-6 vs 142+/-5 ms), as were LVEF (18+/-1 vs 23+/-1%), and peak oxygen uptake during exercise (peak VO(2)) (12.8+/-0.5 vs 15.6+/-0.5 ml/min/kg). While each of these parameters was a risk predictor in univariate analysis, multivariate analysis revealed that HRV provides both independent and additional prognostic information with respect to the risk 'cardiac mortality or deterioration of CHF'. It is concluded that the determination of HRV enhances the prognostic power given by the most widely used parameters LVEF and peak VO(2) in the prediction of mortality or deterioration of CHF and thus enables to improve risk stratification.
    Zeitschrift für Kardiologie 01/2003; 91(12):1003-12. · 0.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This prospective study tested the impact of beta-blocker treatment on currently used risk predictors in congestive heart failure (CHF). Given the survival benefit obtained by beta-blockade, risk stratification by factors established in the "pre-beta-blocker era" may be questioned. The study included 408 patients who had CHF with left ventricular ejection fraction (LVEF) <45%, all treated with an angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist, who were classified into those receiving a beta-blocker (n = 165) and those who were not (n = 243). In all patients, LVEF, peak oxygen consumption (peakVO(2)), plasma norepinephrine (NE) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined. Although the New York Heart Association functional class (2.2 +/- 0.7 vs. 2.3 +/- 0.7), peakVO(2) (14.4 +/- 5.2 ml/min per kg vs. 14.4 +/- 5.5 ml/min per kg) and NT-proBNP (337 +/- 360 pmol/l vs. 434 +/- 538 pmol/l) were similar in the groups with and without beta-blocker treatment, the group with beta-blocker treatment had a lower heart rate (68 +/- 30 beats/min vs. 76 +/- 30 beats/min), lower NE (1.7 +/- 1.2 nmol/l vs. 2.5 +/- 2.2 nmol/l) and higher LVEF (24 +/- 10% vs. 21 +/- 9%; all p < 0.05). Within one year, 34% of patients without beta-blocker treatment, but only 16% of those with beta-blocker treatment (p < 0.001), reached the combined end point, defined as hospital admission due to worsening CHF and/or cardiac death. A beneficial effect of beta-blocker treatment was most obvious in the advanced stages of CHF, because the end-point rates were markedly lower (all p < 0.05) in the group with beta-blocker treatment versus the group without it, as characterized by peakVO(2) <10 ml/min per kg (26% vs. 64%), LVEF < or = 20% (25% vs. 45%), NE >2.24 nmol/l (18% vs. 40%) and NT-proBNP >364 pmol/l (27% vs. 45%), although patients with beta-blocker treatment received only 37 +/- 21% of the maximal recommended beta-blocker dosages. The prognostic value of variables used for risk stratification of patients with CHF is markedly influenced by beta-blocker treatment. Therefore, in the beta-blocker era, a re-evaluation of the selection criteria for heart transplantation is warranted.
    Journal of the American College of Cardiology 05/2002; 39(10):1615-22. · 14.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It was the aim of the present study to characterize the effect of single components of ischaemia, such as inhibition of aerobic and anaerobic energy production by combined anoxic and glucose-free perfusion (metabolic inhibition), high extracellular potassium concentrations (hyperkalaemia), and acidosis, on (1). the stimulated release of noradrenaline from the in situ perfused guinea-pig heart and (2). its presynaptic modulation by the muscarinic agonist carbachol. The release of endogenous noradrenaline from efferent cardiac sympathetic nerve endings was induced by electrical stimulation of the left stellate ganglion (1 min, 5 V, 12 Hz) and quantified in the coronary venous effluent by high-performance liquid chromatography. Under control conditions, two consecutive electrical stimulations (S1, S2) elicited a similar noradrenaline overflow (S2/S1: 0.98 plus minus 0.05). After 10 min of global myocardial ischaemia overflow of endogenous noradrenaline was significantly reduced (S2/S1: 0.18 plus minus 0.03; P< 0.05). When studied separately, metabolic inhibition, hyperkalaemia (16 mM), and acidosis (pH 6.0) each markedly attenuated stimulated noradrenaline overflow (S2/S1: 0.65 plus minus 0.05, 0.43 plus minus 0.14, and 0.37 plus minus 0.09, respectively; P< 0.05). The muscarinic agonist carbachol (10 microM) inhibited stimulated noradrenaline release under normoxic conditions (S2/S1: 0.41 plus minus 0.07; P< 0.05). However, after 10 min of global myocardial ischaemia the inhibitory effect of carbachol on noradrenaline overflow was completely lost. Single components of ischaemia had a differential effect on presynaptic muscarinic modulation. Whereas hyperkalaemia (8-16 mM) did not affect muscarinic inhibition of noradrenaline release, carbachol lost its inhibitory effect during acidosis and metabolic inhibition. In conclusion, hyperkalaemia, metabolic inhibition, and severe acidosis each contribute to reduced overflow of noradrenaline after 10 min of myocardial ischaemia. However, presynaptic muscarinic inhibition of noradrenaline release was not affected by hyperkalaemia, but was sensitive to metabolic inhibition and low degrees of acidosis.
    Pharmacological Research 03/2002; 45(3):221-8. · 4.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The performance of a US-American scoring system (Heart Failure Survival Score, HFSS) was prospectively evaluated in a sample of ambulatory patients with congestive heart failure (CHF). Additionally, it was investigated whether the HFSS might be simplified by assessment of the distance ambulated during a 6-min walk test (6'WT) instead of determination of peak oxygen uptake (peak VO(2)). In 208 middle-aged CHF patients (age 54+/-10 years, 82% male, NYHA class 2.3+/-0.7; follow-up 28+/-14 months) the seven variables of the HFSS: CHF aetiology; heart rate; mean arterial pressure; serum sodium concentration; intraventricular conduction time; left ventricular ejection fraction (LVEF); and peak VO(2), were determined. Additionally, a 6'WT was performed. The HFSS allowed discrimination between patients at low, medium and high risk, with mortality rates of 16, 39 and 50%, respectively. However, the prognostic power of the HFSS was not superior to a two-variable model consisting only of LVEF and peak VO(2). The areas under the receiver operating curves (AUC) for prediction of 1-year survival were even higher for the two-variable model (0.84 vs. 0.74, P<0.05). Replacing peak VO(2) with 6'WT resulted in a similar AUC (0.83). The HFSS continued to predict survival when applied to this patient sample. However, the HFSS was inferior to a two-variable model containing only LVEF and either peak VO(2) or 6'WT. As the 6'WT requires no sophisticated equipment, a simplified two-variable model containing only LVEF and 6'WT may be more widely applicable, and is therefore recommended.
    European Journal of Heart Failure 10/2001; 3(5):577-85. · 5.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to characterize the influence of D,L-sotalol on arterial baroreflex sensitivity (BRS) which is generally considered as an estimate of vagal activity and has prognostic value in patients after myocardial infarction (MI). Conscious rats were studied 3 days after left anterior descending coronary artery ligation (n= 5) or sham-operation (SH, n= 6). BRS was determined by linear regression analysis of the RR-interval (interval between heart beats) and mean arterial pressure changes evoked by i.v. bolus injections of methoxamine (inducing reflex bradycardia, RB) and nitroprusside (inducing reflex tachycardia, RT). In MI-rats heart rate and mean arterial pressure were not significantly different from values in SH-rats, left ventricular end-diastolic pressure was increased and contractility was depressed. The BRS (RB: MI: 0.48 +/- 0.04(*), SH: 0.79 +/- 0.08; RT: MI: 0.41 +/- 0.05(*), SH: 0.86 +/- 0.08 ms mmHg(-1)) ((*)P< 0.05 vs SH) was markedly reduced. d, l -Sotalol (1.5 mg kg(-1)i.v.) reduced heart rate (MI: -11 +/- 3 %(*), SH: -11 +/- 3 %(*)) and mean arterial pressure only moderately [MI: -6 +/- 4 %(n.s.), SH: -7 +/- 2 %(*)], while BRS depression in MI-rats was completely neutralized [RB: MI: 1.08 +/- 0.14(*), SH: 1.19 +/- 0.11(*); RT: MI: 0.84 +/- 0.08(*), SH: 0.88 +/- 0.12 (n.s.) ms mmHg(-1)] ((*)P< 0.05 vs pretreatment). The BRS is reduced in rats early after MI, indicating a depressed reflex vagal activity. Treatment with D,L-sotalol at a dose with little effect on heart rate and mean arterial pressure markedly enhances and, thus, restores BRS in MI-rats. These data suggest that D,L-sotalol has both peripheral and central effects leading to an increase of reflex vagal control of heart rate in rats.
    Pharmacological Research 08/2001; 44(1):13-20. · 4.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Visual evaluation of wall motion is subjective and may be difficult in patients with impaired left ventricular function. Current algorithms used to analyze wall motion usually neglect motion asynchrony that may be profoundly altered in coronary artery disease. This study was to investigate whether the extent of left ventricular asynergy can be used to quantify the severity of regional myocardial dysfunction by the use of Fourier phase imaging. Echocardiographic cine loops of 21 patients with ischemic cardiomyopathy (EF < or = 40%) were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of wall motion as phase angles in parametric images and regional phase histograms. Segmental fractional area shortening (FAC) and qualitative assessment of regional wall motion based on visual inspection served as reference method. There was an inverse linear relationship between FAC and phase angles (r = -0.75, p < 0.01). Normal endocardial motion yielded low phase angles (mean 16 +/- 15 degrees SD). With an increase in wall motion abnormalities, phase angles were progressively delayed by 56 +/- 38 degrees in hypokinetic, by 88 +/- 38 degrees in akinetic, and by 143 +/- 33 degrees (p < 0.001) in dyskinetic segments. These results demonstrate that left ventricular asynchrony is an indicator of regional myocardial dysfunction in coronary artery disease. Echocardiographic Fourier phase imaging can be used to quantify wall motion displaying contraction sequence in a simple and objective format.
    The International Journal of Cardiovascular Imaging 04/2001; 17(2):81-8. · 2.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.
    Journal of the American College of Cardiology 04/2001; 37(4):1049-55. · 14.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 6-min walk test may serve as a more simple clinical tool to assess functional capacity in congestive heart failure than determination of peak oxygen uptake by cardiopulmonary exercise testing. The purpose of the study was to prospectively examine whether the distance ambulated during a 6-min walk test (i) correlates with peak oxygen uptake, (ii) allows peak oxygen uptake to be predicted, and (iii) provides prognostic information similar to peak oxygen uptake in patients with dilated cardiomyopathy and left ventricular ejection fraction < or = 35%. In 113 patients (age: 54+/-12 years, NYHA: 2.2+/-0.8) with dilated cardiomyopathy (left ventricular ejection fraction 19+/-7%) a 6-min walk test and cardiopulmonary exercise testing were performed. The 6-min walk test and peak oxygen uptake were closely correlated at the initial visit (r=0.68, n=113), as well as after 263+/-114 (r=0.71, n=28) and 381+/-170 days (r=0.74, n=14). During serial exercise testing the 6-min walk test allowed peak oxygen uptake to be reliably predicted (r=0.76 between calculated and real peak oxygen uptake). After 528+/-234 days, 42 patients were hospitalized due to worsening heart failure and/or died from cardiovascular causes. Compared to clinically stable patients, these 42 patients walked a shorter distance (423+/-104 vs 501+/-95 m, P<0.001) and had a lower peak oxygen uptake (12.7+/-4.0 vs 17.4 + 5.6 ml x min(-1) x kg(-1), P<0.001). By univariate analysis the 6-min walk test outperformed other prognostic parameters such as left ventricular ejection fraction, cardiac index and plasma norepinephrine concentration and conferred a prognostic power similar to peak oxygen uptake. This predictive value could be further improved in a multivariate model, by combining the 6-min walk test with independent variables, such as left ventricular ejection fraction or cardiac index. The 6-min walk test correlated with peak oxygen uptake when tested serially over the course of the disease. Although both tests define two distinct domains of functional capacity, the 6-min walk test provides prognostic information very similar to peak oxygen uptake in congestive heart failure patients with dilated cardiomyopathy.
    European Heart Journal 04/2000; 21(7):540-9. · 14.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. Both BRS and HRV are reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.
    Cardiovascular Research 04/2000; 45(4):900-12. · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It was the aim of the present study to investigate the influence of Bretschneider's cardioplegia on norepinephrine (NE) release [determined by high pressure liquid chromatography (HPLC) and electrochemical detection] in isolated perfused guinea-pig hearts. The following resulted were noted. (1) Calcium-dependent exocytotic NE release evoked by electrical field stimulation (12 Hz, 1 min) was completely suppressed after only 3 min of normothermic (37.5 degrees C) Bretschneider's cardioplegia. (2) Stop-flow ischemia is associated with a substantial calcium-independent, non-exocytotic NE release, which is regarded as a sodium-dependent carrier-mediated process. Accordingly, it is inhibited by blockers of the sodium/proton-exchanger (e.g. amiloride) and the neuronal uptake1-carrier (e.g. desipramine). Compared with stop-flow ischemia alone, cardioplegia with 3 min of Bretschneider's histidine-tryptophan-ketoglutarate (HTK)-solution preceding stop-flow enhanced NE release at all stop-flow durations (10-90 min) investigated (e.g. after 30 min of normothermic Bretschneider's cardioplegia: 1070+/-41 pmol/g, n = 45, v stop-flow alone: 764+/-48 pmol/g, n = 27, P<0.05). The NE concentrations determined in the cardiac effluent upon reperfusion followed a typical first order kinetic indicating that the transmitter release had already occurred during stop-flow. Hypothermia reduced NE release in a temperature-dependent manner down to intramyocardial temperatures of 2 7.5 degrees C. NE release evoked by Bretschneider's cardioplegia still exceeded that induced by stop-flow ischemia alone by up to 60%. The NE release evoked by Bretschneider's cardioplegia and stop-flow ischemia was calcium-independent. However, it was significantly reduced by desipramine and amiloride, but both agents had a more pronounced inhibitory effect on NE release evoked by stop-flow ischemia alone. (3) This difference may be due to an intrinsic effect of Bretschneider's HTK-solution, as continuous administration of normothermic Bretschneider's HTK-solution induced a substantial NE release which was neither calcium-dependent nor inhibited by blockade of either uptake1 or sodium/proton-exchange. It is concluded that Bretschneider's cardioplegia is not neuroprotective, as it even augments the stop-flow ischemia-induced nonexocytotic NE release.
    Journal of Molecular and Cellular Cardiology 01/1999; 31(1):89-99. · 5.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The baroreflex sensitivity (BRS) and the heart rate variability (HRV) were studied in conscious rats after myocardial infarction (MI; induced by coronary artery ligation) and after sham operation (SH). BRS was determined by linear regression of R-R interval vs. arterial pressure changes induced by nitroprusside or methoxamine (intravenous bolus). HRV was calculated from 3-min electrocardiogram recordings. Left ventricular end-diastolic pressure and plasma atrial natriuretic peptide were increased after MI; plasma norepinephrine and basal heart rate (HR) remained unchanged. At 3 and 28 days after MI, BRS was reduced as indicated by decreased reflex bradycardia (RB) (MI, 0.66 +/- 0.13 and 0.78 +/- 0.07 ms/mmHg; SH, 1.27 +/- 0.16 and 1.48 +/- 0.14 ms/mmHg, respectively; P < 0.05 MI vs. SH). At 56 days after MI, BRS was normalized. RB was unaffected by atropine 3 and 28 days after MI but reduced in all other groups. The increase of basal HR by atropine 3 and 28 days after MI was less than in all other groups. HRV (SD of mean N-N interval, coefficient of variance, low- and high-frequency power; studied at 28 and 56 days) was similar in all groups. It is concluded that BRS is transiently depressed in rats with left ventricular dysfunction after MI probably due to a reduced reflex vagal activity. Even though basal HR and HRV are unchanged after MI, a temporary attenuation of tonic vagal activity is unmasked after autonomic blockade.
    The American journal of physiology 12/1997; 273(5 Pt 2):H2240-7. · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It was the aim of the present study (1) to characterize the influence of Na+/K(+)-ATPase inhibition by the digitalis glycoside ouabain on both spontaneous and nicotine-evoked norepinephrine release from the human heart; and (2) to further investigate the role of glycoside-induced changes in [Na+]i and [Ca2+]i (determined by microfluorimetry) for catecholamine release. The latter experiments were performed in bovine adrenal medullary chromaffin cells (BCC), an established cell culture model for sympathetic nerves. Ouabain (1-1000 mumol/l) exerted a dual effect on norepinephrine release (determined by HPLC) from incubated human atrial tissue: (I) Ouabain induced a concentration-dependent increase in norepinephrine release, that was calcium-independent and almost completely prevented by blockade of the uptake1-carrier by desipramine (1 mumol/l). The characteristics of this release process are consistent with a non-exocytotic mechanism. (II) In addition, ouabain augmented the nicotine-evoked (1-100 mumol/l) calcium-dependent norepinephrine release, which can be considered to be exocytotic. Na+/K(+)-ATPase inhibition also reduced the threshold concentration of nicotine from 10 to 1 mumol/l and it delayed the rapid tachyphylaxis of its norepinephrine releasing effect in human atrial tissue. In BCC, ouabain increased [Na+]i, [Ca2+]i and [3H]-norepinephrine release in parallel. Under calcium-free conditions, not only the ouabain-induced increase in [Na+]i, but also [3H]-norepinephrine release were enhanced. The ouabain-induced [3H]-norepinephrine release was always closely related to changes in [Na+]i, indicating a key role of [Na+]i for this calcium-independent non-exocytotic norepinephrine release. In addition, pretreatment with ouabain (1 mmol/l) augmented the nicotine-evoked (0.1-10 mumol/l) increments in [Na+]i, [Ca2+]i and [3H]-norepinephrine release. As nicotine-induced norepinephrine release depends on an increase in both [Na+]i and [Ca2+]i, these findings are indicative of an ouabain-mediated facilitation of exocytosis. In conclusion, increasing [Na+]i and [Ca2+]i inhibition of Na+/K(+)-ATPase by ouabain triggers non-exocytotic norepinephrine release, and facilitates nicotine-evoked exocytotic norepinephrine release.
    Journal of Molecular and Cellular Cardiology 07/1997; 29(6):1615-27. · 5.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The influence of single components of myocardial ischaemia, such as anoxia, substrate withdrawal, hyperkalemia and extracellular acidosis, on nicotine-induced norepinephrine (NE) release was investigated in the isolated perfused guinea-pig heart, in incubated human atrial tissue and in cultured bovine adrenal chromaffin cells (BCC). In normoxia, nicotine (1-1000 mumol/l) evoked a concentration-dependent release of NE (determined by high pressure liquid chromatography and electrochemical detection) from guinea-pig heart and human atrium. In contrast to selective anoxia (Po2 < 5 mmHg) or glucose withdrawal, respectively, anoxia in combination with glucose withdrawal (5-40 min) markedly potentiated nicotine-induced NE release both in guinea-pig heart and human atrium. The sensitization of cardiac sympathetic nerve endings to nicotine was characterized by a lower threshold concentration and an approximate two-fold increase of maximum NE release, peaking after 10 min of anoxia and glucose withdrawal. Cyanide intoxication (1 mmol/l) combined with glucose withdrawal resulted in a similar increase of nicotine-induced sympathetic transmitter release both in guinea-pig heart and human atrium. In contrast, the nicotine-induced (10 mumol/l) NE overflow was only slightly potentiated by 10 min of global ischaemia in guinea-pig heart. Both hyperkalemia ([K+] 16 mmol/l) and acidosis (pH 6.8-6.0) distinctly attenuated the stimulatory effect of nicotine in guinea-pig heart and human atrium under normoxic conditions. Consistent with an exocytotic release mechanism, NE release was dependent on the presence of extracellular calcium under all conditions tested. Furthermore, NE overflow from guinea-pig heart was accompanied by a release of the exocytosis marker neuropeptide Y (NPY; determined by radioimmunoassay). In BCC, nicotine (1-10 mumol/l) evoked a release of NE and NPY and a transient rise of [Ca2+]i (determined with fura-2) during normoxia which were both dependent on the presence of extracellular calcium. Both hyperkalemia and acidosis markedly reduced the exocytotic release of sympathetic transmitters and the corresponding [Ca2+]i-transients. These data demonstrate that nicotine-induced cardiac exocytotic NE release is markedly potentiated during short-term anoxia in combination with glucose withdrawal. In contrast, a brief period of ischaemia causes only a slight sensitization of cardiac sympathetic nerve endings to nicotine. This discrepancy may be due to an attentuation of nicotine-evoked NE release by hyperkalemia and by acidosis. The protective effect of these factors against anoxia-induced sensitization to nicotine appears to be related to the inhibition of nicotine-evoked [Ca2+]i-transients.
    Journal of Molecular and Cellular Cardiology 09/1995; 27(8):1491-506. · 5.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intracellular free sodium ([Na+]i) and calcium ([Ca2+]i) concentrations were determined by sodium-binding benzofuran isophthalate (SBFI) and fura 2 microfluorimetry, respectively, in bovine adrenal chromaffin cells (BCC). Validation of SBFI microfluorimetry by in vitro and in vivo calibration revealed a reliable assessment of [Na+]i within a range of 1-30 mM in single BCC. Nicotine (0.1-10 microM) induced concentration-dependent increases of both [Na+]i (from 3.3 +/- 0.1 to 25.6 +/- 0.4 mM, n = 76, P < 0.001) and [Ca2+]i (from 64 +/- 1 to 467 +/- 16 nM, n = 87, P < 0.001), which were accompanied by an increase in [3H]norepinephrine (NE) release. Consistent with an exocytotic release mechanism, nicotine-induced increments of [Ca2+]i and [3H]NE release were reduced under calcium-free conditions and by gadolinium chloride (40 microM), whereas [Na+]i was not affected. In contrast, a parallel attenuation of nicotine-evoked changes in [Na+]i, [Ca2+]i, and [3H]NE release was observed during reduction of the extracellular sodium concentration. The nicotine-evoked responses were neutralized by the nicotinic receptor antagonist hexamethonium (100 microM) but not by blockade of voltage-dependent sodium channels (1 microM tetrodotoxin). In conclusion, the nicotine-induced exocytotic release of [3H]NE is triggered by an increase in [Ca2+]i, which is facilitated by sodium influx through the nicotinic receptor ionophore.
    The American journal of physiology 09/1995; 269(3 Pt 1):C572-81. · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It was the aim of the present study to characterize the modulatory effect of muscarinic agonists on the overflow of norepinephrine and neuropeptide Y (NPY) from the in situ perfused guinea pig heart, induced by electrical stimulation of the left stellate ganglion (6 Hz, 5 V, 1 min). The muscarinic agonists oxotremorine (0.01-1 microM) and carbachol (0.1-10 microM) reduced norepinephrine and NPY overflow in a concentration-dependent manner to approximately 30% of control. The inhibitory effect of carbachol was antagonized by the unspecific muscarinic antagonist atropine (1 microM) but not by the nicotinic antagonist hexamethonium (100 microM). The M2-specific antagonist AF-DX-116BS was 25 times more potent than the M1-specific antagonist pirenzepine in antagonizing the inhibitory effect of carbachol [50% inhibitory concentration (IC50) = 0.2 microM for AF-DX-116BS; IC50 = 5.0 microM for pirenzepine]. These findings indicate that presynaptic muscarinic inhibition of stimulated norepinephrine and NPY release from the guinea pig heart is mediated mainly by activation of M2 receptors. As early as 2 min after stop-flow ischemia, the inhibitory effect of carbachol (10 microM) on the stimulation-evoked overflow of norepinephrine and NPY was lost. On reperfusion with oxygenated buffer after 10 min of stop-flow ischemia the inhibitory effect of carbachol (10 microM) on stimulation-induced norepinephrine and NPY overflow recovered within 3 min.
    The American journal of physiology 01/1995; 267(6 Pt 2):R1552-8. · 3.28 Impact Factor