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Biomedical subjects

E Erdmann

Publications and source records attributed to E Erdmann.

At least 181 records · Page 10Linked to original sources
PubMed1995

Myocardial Gi alpha-protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock.

OBJECTIVE: Increased inhibitory G-protein alpha-subunits (Gi alpha) have been reported to be related to adenylyl cyclase desensitization in the failing human heart. In order to investigate whether this cellular alteration occurs already at the stage of hypertensive cardiac hypertrophy or in catecholamine-refractory cardiogenic shock, Gi alpha levels were studied in myocardial samples from patients with hypertensive cardiac hypertrophy, coronary heart disease without heart failure and from patients with cardiogenic shock on high-dose catecholamine therapy as well as from patients without evidence of heart disease. METHODS: Gi alpha was quantified with pertussis-toxin-catalyzed 32P-ADP-ribosylation and with a radioimmunoassay in myocardial samples from patients within 16 h of death. The radioimmunoassay was constructed with recombinant G-protein alpha-subunits (rGi alpha 1) from transformed E. coli harbouring the full-length cDNA of Gi alpha 1, iodinated peptide 125I-KENLKDCGLF and immunoprecipitating antiserum (MB 1) raised against the synthetic peptide (KENLKDCGLF) in rabbits. RESULTS: Pertussis toxin substrates and immunochemical Gi alpha remained stable up to 80 h following storage at room temperature in myocardium obtained during cardiac transplantation. Gs alpha, adenylyl cyclase, beta-adrenoceptors and inhibitory receptors were not stable and could not be determined. Increases in myocardial Gi alpha of 65-82% of both pertussis toxin substrates and immunologically quantified Gi alpha were observed in hypertensive cardiac hypertrophy. Catecholamine therapy in patients who died of catecholamine-refractory shock increased myocardial Gi alpha by 225% compared to myocardium from patients with coronary heart disease without heart failure and without catecholamine therapy or compared to control myocardium. CONCLUSION: These findings provide evidence than an increase in myocardial Gi alpha-proteins could be of relevance in pathological conditions other than chronic heart failure. Since an increase in Gi alpha levels already occurs in hypertensive cardiac hypertrophy, it could play a role in contributing to the development of contractile dysfunction and heart failure in later stages of the syndrome. Finally, an increase in Gi alpha could be one mechanism contributing to catecholamine refractoriness in shock. This could provide a target for pharmacological treatment in this condition.

Autoradiography↗
PubMed1994

Antiadrenergic effect of carbachol but not of adenosine on contractility in the intact human ventricle in vivo.

OBJECTIVES: The purpose of this study was to investigate the antiadrenergic effects of adenosine and carbachol on beta-adrenoceptor-stimulated human ventricular contractility in vivo. In addition, the antiadrenergic effects of adenosine and carbachol were compared in vitro. BACKGROUND: Adenosine is reported to exhibit an antiadrenergic negative inotropic response in the beta-adrenergic-stimulated ventricular myocardium in vitro. The effect of adenosine is similar to the antiadrenergic effect of m-cholinoceptor stimulation in vitro. METHODS: The inotropic response in vivo was assessed in seven healthy volunteers by M-mode echocardiography and simultaneous blood pressure monitoring. It was calculated as the increase in the rate-corrected velocity of circumferential fiber shortening and in the systolic pressure/dimension ratio. All volunteers received pretreatment with 450 mg of dipyridamole/day for 48 h. In addition, the effects of adenosine and carbachol in the presence of 0.03 mumol/liter of isoproterenol on cumulative concentration-response curves of isolated, electrically driven human ventricular muscle strips were compared in vitro (n = 13). RESULTS: The positive inotropic response to continuous infusion of 20 ng/kg per min of isoproterenol (increase of rate-corrected velocity of circumferential fiber shortening [10.2 +/- 2.1% x square root of beats/min per ms] and increase of systolic pressure/dimension ratio 1.09 +/- 0.3 mm Hg/mm) was significantly (p < 0.01) reduced by 3.6 micrograms/kg body weight of intravenous carbachol (4.2 +/- 1.2% x square root of beats/min per ms, 0.21 +/- 0.18 mm Hg/mm) but not by 50 micrograms/kg of intravenous adenosine (8.2 +/- 3.1% x square root of beats/min per ms, 1.35 +/- 0.42 mm Hg/mm), although adenosine induced a significant negative dromotropic effect. In vitro comparison of force of contraction with cumulative concentration-response curves in the presence of 0.03 mumol/liter of isoproterenol demonstrated an EC50 value (concentration producing half-maximal effect) for adenosine 466 times higher than that for carbachol (65.3 vs. 0.14 mumol/liter, p < 0.001). CONCLUSIONS: In contrast to carbachol, adenosine does not attenuate the catecholamine-induced increase in contractility in the human ventricle in vivo. These differences between the A1-adenosine receptor- and m-cholinoceptor-mediated effects could be due to fewer A1-adenosine receptors or a less efficient receptor-effector coupling, or both.

Adenosine↗
PubMed1994

Titin, myosin light chains and C-protein in the developing and failing human heart.

We investigated relative amounts of titin, myosin light chains (MLC), C-protein, and myosin heavy chains (MHC) in the functionally intact contractile apparatus of embryonic, adult normal, and adult failing human left ventricle by SDS polyacrylamide gel electrophoresis and Western blot analysis. The amount of titin and the titin-MHC ratio was significantly (P < 0.05) lower in the embryonic and adult failing human compared to the adult normal fibres. Additionally, we found a protein band having a lower molecular weight but the same immunoreactivity as native titin (fast-migrating titin; FM-titin) in the failing heart only. The MLC-1/MLC-2 ratio was about 1.0 in normal and failing hearts but about 2.0 in the embryonic heart. Relative amount of C-protein was the same in normal and failing fibres but lower in the embryonic ventricles. Length-tension ratio of chemically skinned fibres prepared from terminally failing hearts was impaired compared to normal heart fibres. We conclude that both the reduced titin/MHC ratio and the expression of a structurally different titin form may be involved in the impaired contractile function of the terminally failing human heart.

Carrier Proteins↗
PubMed1994

Changes in cAMP formation in mononuclear leukocytes of heart and renal transplant recipients.

In mononuclear leukocytes (MNL) of renal transplant recipients treated with cyclosporine A and prednisone, an increase of basal cAMP generation has been observed. In order to characterize the mechanisms underlying changes of cAMP generation in patients who were treated with immunosuppressives following heart transplantation, we investigated the beta-adrenoceptor--G protein--adenylate cyclase signal transduction cascade in heart transplant recipients and for comparison in renal transplant recipients as well as controls. Basal cAMP formation in MNL was elevated in heart transplant recipients by 272% and in renal transplant recipients by 148% compared to controls. Following beta-adrenoceptor stimulation with isoprenaline, cAMP formation in MNL of heart transplant recipients was similar to the controls, but was enhanced in renal transplant recipients to 138%. Investigation of beta-adrenoceptor density on MNL as a possible cause for increased cAMP formation revealed similar receptor numbers in controls and in cardiac or renal transplant recipients. Furthermore, the increase of the beta-adrenoceptor density on MNL, which is observed following infusion of isoprenaline, was similar in controls and heart transplant recipients. The amount of pertussis- and cholera toxin substrates was the same in heart transplant recipients as in controls. In contrast, MNL of renal transplant recipients showed a marked increase of Gs alpha by 45% and a smaller albeit significant increase of Gi alpha by 15%, as judged by cholera toxin and pertussis toxin labeling, respectively. Investigation of inotropic parameters by echocardiography under control conditions and during the infusion of increasing concentrations of isoprenaline revealed no difference in the basal contractility and the inotropic response to beta-adrenergic stimulation in controls and heart transplant recipients. It is concluded that changes of G-protein expression are involved in the increase of the cAMP-generation in MNL of heart transplant recipients. These alterations in MNL cannot be taken as a model of cellular function in the transplanted heart, but it is reasonable to suggest that elevations of cAMP formation in MNL may contribute to the immunosuppressive effects of the treatment with cyclosporine A or corticosteroids, the mechanism of which could be an alteration of Gs alpha or the catalyst in renal transplant recipients and the catalyst in heart transplant recipients which occurs without any changes of beta-adrenoceptors.

Adenylate Cyclase Toxin↗
PubMed1994

Intracellular calcium handling in isolated ventricular myocytes from cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure.

Intracellular [Ca2+]i handling has been shown to be altered in isolated ventricular myocytes from patients with terminal heart failure. The aim of this study was to evaluate if alterations of intracellular [Ca2+]i handling and triggering Ca2+ currents in cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure might be similar to changes found in myocytes of patients with terminal heart failure and, therefore if the hamster might serve as a model for heart failure in man. Cells were isolated from hearts of hamsters developing hereditary cardiomyopathy (CMP) (strain BIO 14.6) at 12-14 months of age with overt signs of congestive heart failure. Results were compared with age-matched, undiseased control animals (CTRL). [Ca2+]i transients and Ca2+ currents were recorded simultaneously from isolated cells under voltage clamp perfused internally with the Ca2+ indicator, Fura-2. Ca2+ current densities in myocytes from CMP hamsters were -6.6 +/- 0.6 versus -8.3 +/- 0.5 microA/cm2 (P < 0.05) in CTRL. Resting [Ca2+]i levels were not significantly different. Peak [Ca2+]i transients were significantly decreased in CMP cells (450 +/- 52 nM versus 1031 +/- 98 nM in CTRL, P < 0.05). The rate of diastolic [Ca2+]i decay was slower in cells from CMP animals (t1/2: 167 +/- 19 versus 109 +/- 16 ms; P < 0.05). A moderate negative correlation was found between cell surface area and [Ca2+]i transients (r = 0.42; P < 0.05). It is concluded that changes of intracellular [Ca2+]i handling may play an important role in altered contractility of the myocardium of hamsters with hereditary cardiomyopathy in the late stage of congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Influence of halothane on the effect of cAMP-dependent and cAMP-independent positive inotropic agents in human myocardium.

Volatile anaesthetics have a variety of effects on the myocardium, namely a negative inotropic effect and a catecholamine sensitizing effect. The present study was designed to see if the hydrocarbon anaesthetics interact specifically with subcellular targets of the myocardial cell, by examining the effects of halothane in the presence of positive inotropic agents with different mechanisms of action. Experiments were performed in isolated electrically driven left ventricular preparations (1 Hz, 37 degrees C, Ca2+ 1.8 mmol litre-1) from human hearts obtained at cardiac surgery. The concentration-response curves of noradrenaline, milrinone, BayK 8644 and Ca2+ were investigated in the absence and in the presence of halothane. Halothane enhanced the efficacy of noradrenaline and milrinone but not of Ca2+ or BayK 8644. The potency of milrinone was also increased by halothane, whereas the potency of BayK 8644 was decreased and those of noradrenaline and Ca2+ were unchanged. Halothane differentially influences the effects of agents with different positive inotropic mechanisms. This experimental approach can be taken as a functional method to localize the mechanisms of action of the inhalation anaesthetics in human myocardium, namely sensitization of cAMP formation and interaction with L-type Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

cAMP concentrations, cAMP dependent protein kinase activity, and phospholamban in non-failing and failing myocardium.

OBJECTIVE: Several signal transduction defects such as a reduction of myocardial cAMP formation and an altered intracellular Ca2+ handling have been observed in the failing human myocardium. The aim of the study was to obtain data on changes beyond cAMP formation involving cAMP dependent protein kinase and its substrates. METHODS: cAMP dependent protein kinase activity and cAMP concentrations were measured in the particulate and soluble fraction of failing human hearts (ischaemic, and dilated cardiomyopathy) and non-failing donor hearts. Phospholamban was quantified by cAMP dependent phosphorylation using 32P-ATP as substrate and on western blots using a monoclonal antibody. RESULTS: cAMP concentrations were reduced in the particulate fraction in both ischaemic and dilated cardiomyopathy and in the soluble fraction in dilated cardiomyopathy, but there was no difference in cAMP dependent protein kinase activity. Both phospholamban levels and cAMP dependent phosphorylation of phospholamban were similar in non-failing myocardium and in both ischaemic and dilated cardiomyopathy. CONCLUSIONS: These findings show that the reduction of cAMP formation is the predominant alteration in heart failure, but cAMP dependent protein kinase and phospholamban are evidently unchanged.

Adenosine Triphosphatases↗
PubMed1994

Cardiac norepinephrine, beta-adrenoceptors, and Gi alpha-proteins in prehypertensive and hypertensive spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHR), cardiac adenylate cyclase is desensitized owing to down-regulation of myocardial beta-adrenoceptors and an increase in Gi alpha. We wished to determine whether these biochemical alterations in the beta-adrenoceptor-adenylate cyclase system precede development of hypertensive cardiac hypertrophy or whether this increase occurs only in later stages of the syndrome and represents a secondary phenomenon. Myocardial samples from 5- and 13-week-old SHR and age-matched Wistar Kyoto rats (WKY) as controls were studied. Cardiac beta-adrenoceptors were studied with [125I]cyanopindolol ([125I]ICYP] as radiolabeled ligand. beta-Adrenoceptor subtypes were determined with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively. Gi alpha proteins were measured with the pertussis toxin-catalysed [32P]ADP ribosylation. Myocardial norepinephrine (NE) content was investigated with high pressure liquid chromatography. In myocardial membranes of 13-week-old SHR, the number of total beta-adrenoceptors as well as beta 1- and beta 2-adrenoceptors was reduced. No difference was observed between SHR and WKY, at age 5 weeks. The nonionic detergent Lubrol PX at 0.5% (vol/vol) increased the amount of detectable Gi alpha by a factor of 14. Under these optimal conditions, Gi alpha was increased by 30% in 13-week-old SHR, but not 5-week-old SHR as compared with WKY. Myocardial NE content was increased by 25-35% in both 5- and 13-week-old SHR as compared with WKY. The results showed that nonspecific beta-adrenoceptor downregulation and an increase in Gi alpha occurs in hypertensive cardiac hypertrophy of SHR. In the prehypertensive stage, these changes were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium.

1. The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation. 2. Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5. The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.

Adult↗
PubMed1994

Chronic aortic dissection: comparison of MR Imaging and transesophageal echocardiography.

PURPOSE: To compare the diagnostic value of magnetic resonance (MR) imaging and transesophageal echocardiography (TEE) in the follow-up of chronic dissection of the thoracic aorta. MATERIALS AND METHODS: Follow-up MR imaging and TEE were performed in 25 consecutive patients with aortic dissection. Ten patients had a type I dissection and 15 had a type III dissection. All patients with type I dissection underwent surgical intervention. Ten of 15 type III dissections were managed medically, and five were managed with surgical intervention. RESULTS: Identification of a persisting dissection and differentiation of the true and false lumina were equal with both methods. The arch vessels and all anastomoses in the surgically treated patients could be assessed only with MR imaging. An intimal flap in the aortic root and formation of an aortic thrombus were visualized in more detail with TEE. At least one entry site could be detected with both methods in 86% of the patients. TEE demonstrated small entry sites more frequently. CONCLUSION: MR imaging provides better visualization of anastomoses and easier comparison of serial studies; TEE should be employed if MR findings are equivocal.

Adult↗
PubMed1994

Coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium.

This study investigated the coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium. Carbachol reduced force of contraction in atria and ventricles by 60 and 35% (in the presence of 0.03 microM isoprenaline), respectively. Addition of (-)-N6-(2-phenylisopropyl)adenosine (R-PIA) in the presence of carbachol did not further reduce force of contraction. R-PIA reduced force of contraction less than carbachol in atria (ventricles) by 35% (25%), but addition of carbachol after R-PIA reduced force of contraction further by 35% (15%). Carbachol increased 35S-labeled guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding maximally 14-fold only when GDP was present by an excess of > 100 times [35S]GTP gamma S, while R-PIA increased binding only 2-fold. Activation of [35S]GTP gamma S binding by A1 adenosine receptor and M-cholinoceptor stimulation was antagonized by theophylline and atropine, respectively. Addition of R-PIA to carbachol did not further increase [35S]GTP gamma S binding. Activation of high-affinity [35S]GTP gamma S binding by agonists showed that carbachol activated [35S]GTP gamma S binding to 20 pmol/mg protein [35S]GTP gamma S binding sites, i.e., 25% of the total number of binding sites (80 pmol/mg protein). With R-PIA, activation of high-affinity [35S]GTP gamma S binding could not reliably be detected with this technique. From the number of M-cholinoceptors (atria, 360 fmol/mg protein; ventricle, 270 fmol/mg protein), it is estimated that 1 M-cholinoceptor activates approximately 50-80 G protein alpha-subunits in atria and ventricles, respectively. It is concluded that stimulation of M-cholinoceptors but not A1 adenosine receptors is able to maximally activate a pool of G protein alpha-subunits.(ABSTRACT TRUNCATED AT 250 WORDS)

Atropine↗
PubMed1994

Beta-adrenergic neuroeffector mechanisms in cardiac hypertrophy of renin transgenic rats.

We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2d gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of beta 1-adrenergic receptors, an increase of inhibitory G protein alpha-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein alpha-subunits and beta 2-adrenergic receptors was unchanged. Desensitization of adenylyl cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages.

Adenylyl Cyclases↗
PubMed1994

Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart.

The beta-adrenergic receptor system of the failing human heart is markedly desensitized. We have recently postulated that this desensitization may in part be caused by an increase in beta-adrenergic receptor kinase (beta ARK) expression. beta ARK is thought to effect desensitization by acting in concert with an inhibitor protein, called beta-arrestin. Two isoforms have been identified both for beta ARK and for beta-arrestin. In the present study, we have investigated the expression of the individual isoforms of beta-arrestin and of beta ARK in left ventricles from failing and control human hearts. mRNAs for all four proteins, beta-arrestin-1, beta-arrestin-2, beta ARK-1, and beta ARK-2, were identified in human heart. Quantitation by reverse-transcription polymerase chain reactions showed that in heart failure there were no changes of the mRNA levels for beta-arrestin-1 and beta-arrestin-2, a slight (< 50%) increase of the mRNA for beta ARK-2, and a threefold increase for beta ARK-1 mRNA. At the protein level, beta-arrestin-1 was readily detected by Western blotting in human heart. Its absolute values were approximately 350 fmol/mg cytosolic protein, and its expression was not changed in heart failure. beta-Arrestin-2 levels were too low to be detectable using the same methods. beta ARK levels as determined by enzymatic activity were approximately 20 fmol/mg cytosolic protein (beta ARK-1 plus beta ARK-2) and thus almost 20-fold lower than those of beta-arrestin. beta ARK levels were increased approximately twofold in heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The failing human heart is unable to use the Frank-Starling mechanism.

There is evidence that the failing human left ventricle in vivo subjected to additional preload is unable to use the Frank-Starling mechanism. The present study compared the force-tension relation in human nonfailing and terminally failing (heart transplants required because of dilated cardiomyopathy) myocardium. Isometric force of contraction of electrically driven left ventricular papillary muscle strips was studied under various preload conditions (2 to 20 mN). To investigate the influence of inotropic stimulation, the force-tension relation was studied in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured after stretching the preparations to 150% of the resting length. To evaluate the length-dependent activation of cardiac myofibrils by Ca2+ in failing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction gradually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle length, or cross-sectional area of the muscles between both groups. Pretreatment with ouabain (0.02 mumol/L) restored the force-tension relation in failing myocardium and preserved the force-tension relation in nonfailing tissue. In skinned-fiber preparations of the same hearts, developed tension increased significantly after stretching only in preparations from nonfailing but not from failing myocardium. The Ca2+ sensitivity of skinned fibers was significantly higher in failing myocardium (EC50, 1.0; 95% confidence limit, 0.88 to 1.21 mumol/L) compared with nonfailing myocardium (EC50, 1.7; 95% confidence limit, 1.55 to 1.86 mumol/L). After increasing the fiber length by stretching, a significant increase in the sensitivity of the myofibrils to Ca2+ was observed in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing human myocardium. On the subcellular level, this phenomenon might be explained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.

Calcium↗