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Biomedical subjects

E Erdmann

Publications and source records attributed to E Erdmann.

At least 271 records · Page 15Linked to original sources
PubMed1990

Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium.

The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.Cl and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K1-values, the rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. The new inotropic agents also displaced the binding of 3H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean Ki-values were considerably higher at m-cholinoceptors than at A1 adenosine receptors. The rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. Competition of the A1 adenosine receptor agonist R-PIA to 3H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient nH = 0.63) and revealed two affinity states of the A1 adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient nH = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the super-high affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity.

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NYHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e., NF greater than NYHA II-III greater than NYHA IV). In the presence of norepinephrine, xamoterol produced negative inotropic effects similar to those of the beta-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction, whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV, isoprenaline stimulated adenylate cyclase about twofold but xamoterol, like pindolol or propranolol, had no effect. Experiments with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, showed that the positive inotropic and lusitropic effects of xamoterol were mediated by beta 1-adrenoceptors. Consistently, xamoterol had a selectivity of 13.8 at beta 1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a beta 1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity, as it produces beta 1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as beta 1-adrenoceptor downregulation of an increase of Gi (inhibitory guanine-nucleotide binding protein).

Adenylyl Cyclases↗
PubMed1990

Improvement of cholera toxin-catalyzed ADP-ribosylation by endogenous ADP-ribosylation factor from bovine brain provides evidence for an unchanged amount of Gs alpha in failing human myocardium.

The aim of the present study was to investigate whether or not alterations of Gs alpha can be detected with cholera toxin-induced ADP-ribosylation in myocardial membranes from patients with heart failure. Therefore, Gs alpha was radiolabeled by cholera toxin-catalzyed (32P)ADP-ribosylation with (32P)NAD as substrate. In membranes from left ventricular myocardium of six patients with dilated cardiomyopathy classified as NYHA IV and three samples from two non-failing donor hearts, labeling was too weak to allow detection of possible changes in the amount of Gs alpha. Therefore, the cytosolic small molecular weight G protein ARF (ADP-ribosylation factor), a cofactor for cholera toxin-induced ADP-ribosylation of Gs alpha, was partially purified from bovine cerebral cortex. ARF activity was quantified by its ability to enhance auto-ADP-ribosylation of cholera toxin A1-subunit. Gs alpha was identified by comparing the ADP-ribosylation patterns of myocardial membranes, membranes prepared from human leukemia (HL 60) and S 49 mouse lymphoma wild type cells (45 kDa-band present) with membranes of the Gs alpha-deficient S 49 variant cyc- (45 kDa-band missing). In the presence of ARF, specific radiolabeling of the Mr 45,000 subtype of Gs alpha was markedly enhanced. The amounts of Gs alpha as measured by cholera toxin-dependent (32P)-ADP-ribosylation in the presence of ARR were similar in failing and nonfailing human hearts. It is concluded that factors other than Gs alpha are responsible for the altered regulation of the adenylate cyclase complex in heart failure. Moreover, by enhancing cholera toxin-catalyzed ADP-ribosylation, endogenous ADP-ribosylation factor from bovine brain appears to be a useful tool to study Gs alpha even in tissues in which the labeling of Gs alpha is rather weak.

ADP-Ribosylation Factors↗
PubMed1990

Calcium sensitivity and myosin light chain pattern of atrial and ventricular skinned cardiac fibers from patients with various kinds of cardiac disease.

In the present study, the Ca2(+)-sensitivity and myosin light chain patterns of skinned fibers of right atrium and left papillary muscles of 27 patients suffering from mitral valve disease (MVD, moderate heart failure), ischemic cardiomyopathy (ICM, severe heart failure), dilated cardiomyopathy (DCM, severe heart failure), and coronary heart disease (CHD, no heart failure, no atrial hypertrophy) were investigated. Myosin light chains of both chemically skinned and intact samples were studied by two-dimensional gel electrophoresis (2D-PAGE). Ca2(+)-sensitivity of ventricular fibers was about 0.14 pCa-units higher than that of atrial fibers in all groups except dilated cardiomyopathy where this difference was markedly diminished (only 0.06 pCa-units). Generally, Ca2(+)-sensitivity of skinned ventricular fibers was the same among the different heart diseases. Skinned atrial fibers from patients with dilated cardiomyopathy, however, were significantly (about 0.08 pCa-units) more sensitive for Ca2+ than those of the other groups (coronary heart disease, mitral valve disease or ischemic cardiomyopathy) which showed similar Ca2(+)-tension relationships. Ventricle-specific P-light chain forms could be observed in atrial samples from patients of all groups, whereas no atrium-specific light chain forms were detectable in any ventricular sample. It is concluded that there is no difference in Ca2(+)-sensitivity of the ventricular contractile elements of the human heart in different heart diseases. In atrial myocardium, there is an increased Ca2(+)-sensitivity of skinned fibers from hearts with dilated cardiomyopathy which is probably related to an elevation of right atrial pressure.

Calcium↗
PubMed1990

Evidence against spare or uncoupled beta-adrenoceptors in the human heart.

It is well established that increasing degrees of heart failure are accompanied by a reduced density of myocardial beta-adrenoceptors. It is unclear, however, whether all beta-adrenoceptors in the cardiac cell membrane are coupled to the effector system or whether "spare receptors" or "uncoupled" beta-adrenoceptors also exist. To investigate this, we measured the density of beta-adrenoceptors and the positive inotropic response to isoprenaline in preparations from the same human hearts. The myocardium from nonfailing hearts had significantly (p less than 0.01) higher numbers of beta-adrenoceptors (104 +/- 7 fmol/mg protein) compared with tissue from moderately (mitral valve disease, New York Heart Association [NYHA] class II to III, 60 +/- 2.8 fmol/mg protein) and terminally (dilated cardiomyopathy, NYHA class IV, 35 +/- 2.7 fmol/mg protein) failing human hearts. The KD values of the drug-receptor complexes did not differ within the different patient groups. There was a linear relationship (r = 0.97) between the beta-adrenoceptor density measured and the maximally obtainable positive inotropic effect elicited by isoprenaline in the three groups tested. Thus there seem to be no spare beta-adrenoceptors, that is, receptors not required for the production of the maximal inotropic response in the left ventricular human myocardium, and there are no uncoupled beta-adrenoceptors. The beta-adrenoceptors associated with the plasma membrane (marker: 3H-ouabain binding sites) remained functionally active. In addition, these results indicate that either there is no amplifier system behind the receptor level or it remains unchanged in the failing left ventricular human myocardium under the conditions tested.

Adrenergic beta-Antagonists↗
PubMed1990

The effect of xamoterol in failing human myocardium.

As the dual pharmacological action of partial beta 1-adrenoceptor agonists should improve left ventricular function while also protecting the myocardium against excessive sympathetic stimulation they may be useful in the treatment of heart failure. Therefore, we studied the pharmacological effects of xamoterol (Corwin, ICI 118, 587), a compound with mixed agonist and antagonistic properties at cardiac beta-adrenoceptors in electrically driven human papillary muscle strips from failing human hearts. Specimens were obtained from patients with different grades of myocardial failure who underwent mitral valve replacement (NYHA II-III) or heart transplantation (NYHA IV). Xamoterol (0.0001-100 mumol l-1) produced only negative inotropic effects, as measured by changes in isometric force of contraction in diseased human papillary muscle strips. However, isoprenaline (0.0001-10 mumol l-1) and ouabain (0.01-0.3 mumol l-1) enhanced force of contraction in the same hearts. Prestimulation with noradrenaline (3 mumol l-1) augmented the negative inotropic effect of xamoterol. It is concluded that xamoterol exerts primarily beta-adrenoceptor antagonistic activity in the failing human myocardium.

Adrenergic beta-Agonists↗
PubMed1990

Effectiveness of cardiac glycosides in human myocardium with and without "downregulated" beta-adrenoceptors.

We investigated the "receptor-effector-coupling" in the beta-adrenoceptor- and the Na+, K(+)-ATPase-mediated systems in nonfailing hearts and terminally failing human myocardium from patients with cardiomyopathy. The density of beta-adrenoceptors in the failing human myocardium was significantly (p less than 0.01) lower as compared with nonfailing hearts, whereas the receptor density and affinity measured by [3H]ouabain binding (cardiac glycoside receptor) was not different in either group. The maximal inotropic response to isoprenaline was significantly reduced in papillary muscle strips from failing human hearts (2.1 +/- 0.5 mN) as compared with control hearts (8.0 +/- 1.0 mN; p less than 0.05). Ouabain remained effective in both groups (6.8 +/- 1.0 vs. 5.5 +/- 0.6 mN; NS). The positive inotropic response due to extracellular Ca2+ elevation (1.8-15 mM) was studied for comparison. Maximal Ca2+ effects were reduced by 30% in failing human myocardium (7.2 +/- 0.5 mN vs. 5.1 +/- 0.8 mN, p less than 0.05). Ouabain had effectiveness (95%) similar to that of Ca2+ in nonfailing and failing human cardiac muscle. It is concluded that treatment with cardiac glycosides may still be effective in end-stage heart failure with "downregulated" beta-adrenoceptors, as judged from these in vitro studies.

Adult↗
PubMed1990

Negative inotropic properties of isradipine, nifedipine, diltiazem, and verapamil in diseased human myocardial tissue.

We investigated the inotropic responses to Ca2+ antagonists using electrically driven human papillary muscle strips and human auricular trabeculae. Specimens were obtained during cardiac surgery for mitral valve replacement [New York Heart Association (NYHA) Class II-III] or heart transplantation (NYHA IV) and during aortocoronary bypass operations. The inotropic effects were studied with cumulative concentration-response curves. All Ca2+ antagonists tested significantly (p less than 0.05) depressed force of contraction at concentrations above 0.01 mumol/L, but their potencies were different. A 50% reduction of the initial force of contraction occurred at the following concentrations (NYHA II-III): nifedipine (mean IC50) 0.09 mumol/L isradipine 0.12 mumol/L, diltiazem 0.69 mumol/L, and verapamil 0.79 mumol/L. There were no significant differences in the negative inotropic effects of any tested Ca2+ antagonist between NYHA II-III and NYHA IV. When the initial force of contraction was reduced by 90%, addition of Ca2+ increased force of contraction significantly less after diltiazem (2.76 +/- 0.4 mN), isradipine (1.82 +/- 0.23 mN), and nifedipine (1.68 +/- 0.25 mN) compared to control (4.63 +/- 0.56 mN) (NYHA II-III). The negative inotropic potencies of nifedipine and verapamil were significantly greater in human auricular trabeculae compared to papillary muscle strips (p less than 0.05). However, on the relation between therapeutic vasoactive plasma concentrations and IC25 values, an entirely different rank order of potential negative inotropism could be observed: verapamil greater than nifedipine greater than diltiazem greater than isradipine.

Adult↗
PubMed1990

Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy.

In myocardial membranes from hearts with dilated cardiomyopathy (DCM), there was a 37% increase of the Gi alpha-protein as measured by 32P-ADP-ribosylation of a approximately 40 kDa pertussis toxin substrate. Immunoblotting techniques also showed increased amounts of Gi alpha in DCM. In hearts with ischemic cardiomyopathy (ICM), Gi alpha was not altered compared with nonfailing myocardium (NF). Basal and Gpp(NH)p-stimulated adenylate cyclase activity was reduced in DCM but not in ICM. The number of beta-adrenoceptors was similarly reduced both in DCM and ICM compared with NF. Alterations of m-cholinoceptors or A1-adenosine receptors did not occur. Consistently, "indirect" negative inotropic effects of the m-cholinoceptor agonist carbachol and the A1-adenosine receptor agonist R-PIA were not different in ICM, DCM, and nonfailing myocardium. In ICM and DCM, there was a marked reduction of the positive inotropic responses to isoprenaline and milrinone. However, there was a further reduction in DCM compared with ICM. It is concluded that the increase of Gi alpha is accompanied by a reduction of basal and guanine-nucleotide-stimulated adenylate cyclase activity. Alterations of m-cholinoceptors and A1-adenosine receptors do not appear to be involved. The further decrease of the positive inotropic effects of isoprenaline and milrinone in DCM provides evidence that the increase of Gi alpha is functionally relevant in DCM but not ICM and hence might contribute to the reduced effects of endogenous catecholamines and exogenous cAMP-dependent positive inotropic agents in the former but not the latter condition.

Adenosine Diphosphate Ribose↗
PubMed1990

Beta 2-adrenoceptors in human lung and peripheral mononuclear leukocytes of untreated and terbutaline-treated patients.

Beta 2-adrenoceptor agonists act against bronchoconstriction by stimulating beta 2-adrenoceptors in bronchial smooth muscle. However, tachyphylaxis has been argued to occur because of beta 2-adrenoceptor down-regulation following therapy with beta 2-adrenergic agents. To investigate receptor alterations, human peripheral mononuclear leukocytes are frequently used, since human lung tissue is not easily available. In order to study whether beta 2-adrenoceptors in MNL reliably reflect the conditions in the human lung tissue, we compared MNL and human lung tissue of 18 patients who had to undergo lung resection. Ten patients were untreated, and eight had bronchodilator therapy prior to therapy with terbutaline because of bronchoconstriction. Both in human lung and MNL, the beta 2-adrenoceptor subpopulation was characterized by competition experiments with the beta 1-selective antagonist CGP 207.12 A and the beta 2-selective antagonist ICI 118.551. In MNL, a significant decrease in the density of beta 2-adrenoceptors was found in treated but not in untreated patients, while the antagonist affinity of the beta 2-adrenoceptors remained unchanged. However, in lung parenchyma, which was obtained at the very same time from the same patients, no down-regulation of the total amount of beta 2-adrenoceptors could be measured. It is concluded that MNLs are a reliable model for studying properties of beta 2-adrenoceptor regulation. However, the hereby obtained results show that MNLs do not reflect the conditions of beta 2-adrenoceptors in human lung tissue. Human lung tissue is found to be less susceptible than human MNL for beta 2-adrenoceptor down-regulation by terbutaline treatment at therapeutic doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Beta-blocking agents and positive inotropic agents in the therapy of chronic heart failure.

Positive inotropic stimulation of the failing cardiac muscle seems to be useful, if certain requirements are met: (a) there is some cardiac contractile reserve left, (b) the positive inotropic agent of choice is able to mobilize this contractile reserve, and (c) peripheral vascular resistance is not increased permanently by this agent. On the other hand, the physiological response (i.e., positive inotropic effect) to circulating catecholamines in heart failure is decreased or even absent due to receptor desensitization and an alteration of guanine nucleotide-binding proteins (increased Gi). It has been proved that functionally active beta-adrenoceptors may be restored by treatment with beta-adrenoceptor antagonists. However, these agents necessarily will have negative inotropic effects in the failing cardiac muscle, if the force of contraction is largely dependent on a permanent stimulation by catecholamines and if there are no spare beta-adrenoceptors. To clarify these as-yet unresolved problems, we have determined the contractile reserve as well as its utilization by positive inotropic agents in human cardiac muscles of failing and nonfailing hearts. The number and functional activity of cardiac glycoside receptors, beta-adrenoceptors, and alpha-adrenoceptors were measured as well as the positive inotropic and negative inotropic effects of partial agonists. Furthermore, we have accumulated evidence that, in fact, there are no spare beta-adrenoceptors in the human cardiac muscle. The lack of spare beta-adrenoceptors has consequences for the therapeutic approach in patients with heart failure. At least initially, the administration of beta-adrenoceptor-blocking agents to patients with heart failure depending on agonist-induced stimulation will lead to a worsening of cardiac function. If this situation can be tolerated, however, the subsequent restoration of functionally active beta-adrenoceptors after beta-blockade may lead to restored physiological regulation of force of contraction by norepinephrine.

Adrenergic beta-Antagonists↗
PubMed1990

Myocardial beta-adrenoceptors and inhibitory G-proteins in myocardial biopsies and in explanted hearts from patients with dilated cardiomyopathy.

Cardiac beta-adrenoceptors and the alpha-subunits of the inhibitory guanine-nucleotide binding proteins (Gi alpha) were determined in myocardial biopsies and in larger samples of explanted hearts from patients with dilated cardiomyopathy. The myocardium of one non-failing heart was studied for comparison. There were fewer beta-adrenoceptors in right and left ventricular samples from hearts with dilated cardiomyopathy than in the non-failing myocardium. The number of beta-adrenoceptors determined by equilibrium saturation experiments closely correlated with their density as measured by a saturating concentration of the radioligand 125Iodocyanopindolol in myocardial biopsies. Using the 32P-ADP-ribosylation of a 40kDa membrane protein catalyzed by pertussis toxin, an increase of Gi alpha could also be shown in both myocardial biopsies and explanted hearts.

Biopsy↗