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Biomedical subjects

E Erdmann

Publications and source records attributed to E Erdmann.

At least 163 records · Page 9Linked to original sources
PubMed1996

Enantioselective inotropic actions of the Na+-channel activators BDF 9148, BDF 9196 and BDF 9167 in human failing and nonfailing myocardium.

Our study investigated the inotropic effect of the novel Na+-channel activator BDF 9148 and its enantiomeres [S(-)BDF 9169, R(+)BDF 9167] in human failing [New York Heart Association Class (NYHA IV) heart transplants, n = 15] and nonfailing myocardium (NF, donor hearts, n = 5). We studied the effect of BDF 9148 (BDF, 0.03-10 micromol/liter) and of its enantiomeres [S(-) BDF 9196; R(+)BDF 9167] on isometric force of contraction (1 Hz) as well as on the force-frequency-relationship (0.5-3 Hz) in electrically driven (37 degrees C) left ventricular papillary muscle strips, BDF and S-BDF, but not R-BDF, increased force of contraction in a dose-dependent manner in NYHA IV and NF. The effectiveness of BDF, S-BDF and Ca2+ (15 mmol/liter) to increase force of contraction was similar in human nonfailing and failing myocardium. The potency of BDF and S-BDF to increase force of contraction was significantly higher in NYHA IV compared to NF. Carbachol (1 mmol/liter) did not affect the positive inotropic response of the studied compounds. In the presence of 3 micromol/liter BDF or S-BDF force of contraction increased after an increase in stimulation frequency only from 0.5 to 1 Hz in NYHA IV and human nonfailing myocardium. At frequencies above 1 Hz the force-frequency-relationship was negative in human nonfailing myocardium and NYHA IV in the presence of high concentrations of BDF or S-BDF. These results suggest that the racemic Na+-channel activator BDF 9148 and the S(-) BDF-enantiomere, but not the R(+) BDF-enantiomere, are effective to increase force development maximally in NYHA IV and in nonfailing myocardium. Human failing myocardium exerts an enhanced sensitivity toward the Na+-channel activator BDF 9148 and its S(-) enantiomere to increase force of contraction when compared to nonfailing tissue. As Na+-channel activators increase force in a frequency-dependent mode of action the force-frequency-relationship may depend on the intracellular Ca2+- and Na+- homeostasis.

Azetidines↗
PubMed1996

[Altered calcium homeostasis in chronic heart failure].

Intracellular calcium homoeostasis is greatly altered in heart failure. This does not seem to be due to altered calcium influx through L-type calcium channels but rather due to altered calcium uptake mechanisms of the sarcoplasmic reticulum. Recently, a negative force-frequency behaviour of the human myocardium has been detected in hearts from patients with severe heart failure. In the myocardium from these patients, SR-Ca(2+)-ATPase activity was decreased. The same defect has been reported in human isolated cardiac myocytes. A disturbed calcium release from the SR may also contribute to this finding of the inverse force-frequency-relationship in the failing myocardium. The altered intracellular calcium handling is connected with the diastolic and systolic failure of the myocardium. Mg++ and Na(+)-channel modulators are able to restore the positive force-frequency-relationship even in severely failing myocardium.

Calcium↗
PubMed1996

[Beta-blockers and heart failure--a critical view].

Recently, several randomised controlled studies have demonstrated improvement in survival of patients with non ischemic cardiomyopathy (Bisoprolol, Metoprolol, Carvedilol) and ischemic cardiomyopathy (Carvedilol). It is not quite clear, whether the observed difference in mortality after beta-blockade on top of diuretics, digitalis and ACE-inhibitors is due to some as yet unknown pathophysiological changes. Certainly, beta-blocking agents have an established efficacy in arrhythmia. Irrespective of the acknowledged benefit in survival, one should note, that the risk reduction in mortality by 65% by Carvedilol has to be viewed critically-as the risk reductions in several other large scale trials. If the mortality in the group receiving digitalis, diuretics and ACE-inhibitors was 7.8%, the mortality after addition of Carvedilol was 3.2%. This means a difference of 4.6%. If however, percent from percent is calculated, than the risk reduction amounts to 65%. One can easily understand, why this larger latter, number usually is being published.

Adrenergic beta-Antagonists↗
PubMed1995

Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.

BACKGROUND: The aim of the present study was to investigate whether Ca2+ uptake into the sarcoplasmic reticulum (SR) is altered in failing human myocardium resulting from dilated cardiomyopathy. METHODS AND RESULTS: Ca(2+)-ATPase (SERCA II) activity and Ca(2+)-dependent 45Ca2+ uptake (oxalate supported, steady state) in isolated vesicles from the SR (VSR) and in crude membrane preparations (CSR) (free Ca2+, 0.01 to 100 mumol/L) from nonfailing (donor hearts, n = 13) and terminally failing (heart transplants, dilated cardiomyopathy, n = 17) human myocardium were studied. In the same hearts, protein levels (Western blot analysis) and mRNA levels (Northern blot analysis) of SERCA II and phospholamban were measured. Increasing concentrations of Ca2+ were followed by an increased Ca(2+)-ATPase activity and Ca2+ uptake. Ca2+ uptake activity and Ca(2+)-ATPase activity in CSR preparations from failing myocardium were significantly reduced compared with nonfailing hearts (Ca(2+)-ATPase, 163 +/- 8 and 125 +/- 7 nmol ATP/mg protein per minute for nonfailing tissue and failing tissue in New York Heart Association [NYHA] class IV, respectively; Ca2+ uptake, 7.1 +/- 0.8 and 3.5 +/- 0.3 nmol/mg protein per minute in CSR from nonfailing and NYHA class IV hearts, respectively P < .05). In contrast, no significant difference was measured in VSR. In the same preparations (CSR and VSR), both SERCA II and phospholamban levels (Western blot technique with monoclonal antibodies) were unchanged in failing compared with nonfailing tissue. mRNA expression relative to GAPDH mRNA for SERCA IIa and for phospholamban was significantly reduced in failing human myocardium (P < .05). CONCLUSIONS: These findings provide evidence that in failing human myocardium caused by dilated cardiomyopathy, protein levels of SERCA II and phospholamban are unchanged even though mRNA levels for SERCA II and phospholamban and the SERCA II function are reduced compared with nonfailing myocardium.

Adenosine Triphosphatases↗
PubMed1995

Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction.

BACKGROUND: Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction were examined in an animal model with beta-adrenergic desensitization, which has been identified in failing hearts and in hypertensive cardiac hypertrophy. It is unknown whether beneficial ACE-inhibitor effects are due to an unloading of the failing heart or a reduction of neuroendocrine activation with beta-adrenergic resensitization. METHODS AND RESULTS: Low-dose (LD, 1 mg/kg) and high-dose (HD, 25 mg/kg) fosinopril treatment was performed in spontaneously hypertensive rats (SHR) and control (WKY) rats. Myocardial norepinephrine concentrations, adenylyl cyclase activity, beta-adrenergic receptors (radioligand binding), Gs alpha (functional reconstitution), and Gi alpha (pertussis toxin labeling) were determined. Ventricular weights and blood pressures were measured. HD but not LD reduced blood pressure and left ventricular weights in SHR. Isoprenaline- and guanylylim-idodiphosphate-stimulated adenylyl cyclase activities as well as beta 1-adrenergic receptors were reduced in SHR. The catalyst and Gs alpha were unchanged, but Gi alpha and norepinephrine concentrations were increased. Both LD and HD treatments restored beta-adrenergic alteration. CONCLUSIONS: LD treatment with ACE inhibitors restored beta-adrenergic signal transduction defects independently of regression of cardiac hypertrophy. This could contribute to the effects of ACE inhibitors in patients, who are often treated with nonhypotensive doses.

Adenylyl Cyclases↗
PubMed1995

Altered diastolic [Ca2+]i handling in human ventricular myocytes from patients with terminal heart failure.

To investigate whether the slow diastolic decay of [Ca2+]i in myocardium of patients with heart failure is a result of alterations of the Ca2+ adenosine triphosphatase of the sarcoplasmic reticulum of the sarcolemma, [Ca2+]i transients were recorded in voltage-clamped ventricular cells isolated from hearts of patients with terminal heart failure or from undiseased donor hearts. To isolate the [Ca2+]i-reuptake function of the sarcoplasmic reticulum, myocytes were dialyzed via the patch pipette with Na(+)-free solution and incubated in Ca(2+)-free and Na(+)-free solution to inhibit Na+/Ca2+ exchange. After superfusion with Ca(2+)-containing, Na(+)-free medium, the sarcoplasmic reticulum was loaded with Ca2+ through repetitive voltage-clamp pulses to +10 mV. Under these conditions, [Ca2+]i decay was significantly slower in myocytes from patients with heart failure (538 +/- 66 msec) than in controls (305 +/- 16 msec; p < 0.05). After the addition of 10 mmol/L of caffeine, [Ca2+]i levels did not show appreciable decay between two voltage-clamp pulses in diseased and undiseased myocytes. We conclude that diastolic decay of [Ca2+]i in ventricular myocytes from patients with terminal heart failure is partially the result of a decreased rate of Ca2+ reuptake by the sarcoplasmic reticulum. Sarcolemmal Ca2+ adenosine triphosphatase does not contribute significantly to cytoplasmic [Ca2+]i removal during an individual heartbeat.

Calcium↗
PubMed1995

Evidence for reduction of norepinephrine uptake sites in the failing human heart.

OBJECTIVES: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.

Adult↗
PubMed1995

Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure.

PURPOSE: The aim of the study was to investigate the mechanisms of myocardial catecholamine refractoriness in septic shock. METHODS: The inhibitory guanine nucleotide-binding proteins (Gi alpha) were studied with pertussis toxin labeling and radioimmunologically in myocardium from patients who died while in catecholamine-refractory septic shock and from patients who died of noncardiac disease. RESULTS: An increase by 62% (immunological Gi alpha) and 221% (pertussis toxin substrate) of myocardial Gi alpha was observed in patients with catecholamine-refractory shock compared with controls. The increases of Gi alpha were greater than those found in chronic heart failure reported earlier. CONCLUSIONS: An increase in the expression of Gi alpha could also be important in conditions other than chronic heart failure, eg, septic shock. An increase of Gi alpha could play a pathophysiologically relevant role in catecholamine refractoriness in septic shock and could provide a target for pharmacologic treatment in this condition.

Adult↗
PubMed1995

Digitalis--friend or foe?

The therapeutic efficacy of cardiac glycosides is not widely appreciated either in respect of their positive inotropic value or antiarrhythmic activity. Although cardiac glycosides do not prevent an increase in ventricular rates during exercise they do slow the heart rate at rest in patients with atrial fibrillation. The clinical importance of the potentially beneficial influence of the digitalis glycosides on the negative force-frequency relationship (Bowditch effect), preload-force relationship (Frank-Starling's Law) and baroreceptor dysfunction in heart failure await clarification. In patients with heart failure, the positive inotropic effects of the digitalis glycosides are mild, but show no tolerance during prolonged administration. Digitalis glycosides are the only group of positive inotropic drugs that persistently increase the ejection fraction during long-term administration in patients with heart failure. These haemodynamic benefits are translated into decreased symptoms and increased exercise capacity in patients with congestive heart failure. Although their clinical efficacy in the different stages of heart failure remains undefined, recent evidence indicates that their therapeutic benefit is on a par with diuretics and ACE inhibitors in symptomatic heart failure. Results of studies specifically directed to determining the impact of the cardiac glycosides on prognosis are awaited.

Anti-Arrhythmia Agents↗
PubMed1995

Treatment in hypertensive cardiac hypertrophy, I. Neuropeptide Y and beta-adrenoceptors.

In the present study, we investigated serum and myocardial neuropeptide Y concentrations as measures of sympathetic activity as well as myocardial beta-adrenoceptors and beta-adrenoceptor-stimulated adenylyl cyclase activity in spontaneously hypertensive rats (SHR). SHR and control rats at 10 weeks of age were kept on oral treatment with captopril, nitrendipine, or both for 20 weeks. Treatment only slightly reduced but did not normalize blood pressure and cardiac hypertrophy in SHR. The elevated serum concentration of neuropeptide Y, the reduced number of beta-adrenoceptors, and the depressed beta-adrenoceptor-stimulated adenylyl cyclase activity were partly normalized compared with the values observed in control rats. We conclude that antihypertensive treatment, at doses that failed to normalize systolic pressure and to reverse cardiac hypertrophy completely, is able to reduce sympathetic activity in SHR, thereby resensitizing the depressed beta-adrenoceptor-adenylyl cyclase system.

Adenylyl Cyclases↗
PubMed1995

Treatment in hypertensive cardiac hypertrophy, II. Postreceptor events.

We investigated the effect of pharmacological treatment with captopril, nitrendipine, and captopril plus nitrendipine on myocardial heterologous adenylyl cyclase desensitization and the underlying postreceptor defects in spontaneously hypertensive rats (SHR). In myocardial membranes from SHR, stimulation of adenylyl cyclase with guanylylimido-diphosphate (P < .001) and forskolin (P < .05) was significantly reduced, whereas no difference with forskolin was obtained in the presence of manganese chloride. Reconstitution of Gs alpha into Gs alpha-deficient S49 cyc- mouse lymphoma cells revealed no difference between SHR and control rats. In contrast, pertussis toxin labeling of Gi alpha was significantly increased in SHR. The reduction of adenylyl cyclase in SHR was abolished after pertussis toxin treatment of membranes. Treatment with captopril, nitrendipine, or both reduced Gi alpha and increased guanylylimidodiphosphate-stimulated adenylyl cyclase activity in SHR. In summary, heterologous adenylyl cyclase desensitization due to an increase of Gi alpha but in the presence of an unchanged activity of Gs alpha or the catalyst occurs in SHR. This alteration, which could contribute to the progression of contractile dysfunction by producing adrenergic subsensitivity, is sensitive to pharmacological treatment most likely because of a reduction of sympathetic activity.

Adenosine Diphosphate Ribose↗