Search PubMed⌕ Search

Biomedical subjects

E Erdmann

Publications and source records attributed to E Erdmann.

At least 379 records · Page 21Linked to original sources
PubMed1984

Cardiac glycoside receptors in cultured heart cells--I. Characterization of one single class of high affinity receptors in heart muscle cells from chick embryos.

Binding of (3H)-ouabain and ouabain-induced inhibition of the sodium pump and of the (Na+ + K+)-ATPase have been characterized in cultured cardiac muscle and non muscle cells, as well as in cardiac cell membranes--all obtained from chick embryos. In both cell types, ouabain binds to a single type of binding sites in a temperature-dependent manner. The association rate but not the dissociation rate, is lowered by K+; specific binding is lost after heat-denaturation of the cells. Binding parameters (association and dissociation rate constants, activation energies for association and dissociation) are similar in muscle and non muscle cells. The dissociation constant of specific ouabain binding is 1.5 X 10(-7)M in cardiac muscle cells, and 1.9 X 10(-7)M in cardiac non muscle cells, the binding capacity being 2.6 and 2.1 pmoles/mg protein respectively. Specific binding of ouabain to the cells is coupled to inhibition of the sodium pump, as can be seen from ouabain-induced inhibition of active (86Rb+ + K+)-uptake, decrease in cellular K+, and increase in cellular Na+ (EC50 = 10(-7)-10(-6)M). The data obtained with cardiac cells are in good agreement with results found for ouabain binding (dissociation constant 4.3 X 10(-7)M) and (Na+ + K+)-ATPase inhibition (EC50 = 1.4 X 10(-6)M) in cardiac cell membranes prepared from the same tissue. Due to the experimental evidence it is concluded that the binding site for ouabain is identical with the cardiac glycoside receptor of these cells. In cardiac non muscle cells, binding of ouabain to its receptor is strictly coupled to inhibition of active K+-transport in a stoichiometric manner. In cardiac muscle cells, however, active K+-transport is inhibited by less than 10% when up to 40% of cardiac glycoside receptors have bound ouabain. It is assumed that this non-stoichiometric coupling of receptor occupancy and sodium pump inhibition in cardiac muscle cells may prevent substantial changes of Na+- and K+-contents in the heart in the presence of therapeutic levels of cardiac glycosides.

Animals↗
PubMed1984

Two receptors for cardiac glycosides in the heart.

Specific binding of 3H-ouabain to rat cardiac cell membranes revealed a high affinity and a low affinity site. In order to test the pharmacological significance of these different types of binding sites, specific 3H-ouabain binding, force of contraction and 86Rb+-uptake were measured simultaneously in contracting cat papillary muscles and in guinea pig atria. The results in the digitalis sensitive cat shows one type of cardiac glycoside receptors with high affinity (KD approximately 10(-7) M) for ouabain. The occupation of this receptor runs parallel with an increase in force of contraction and an inhibition of 86Rb+-uptake. In the rather digitalis insensitive guinea pig, 3H-ouabain binding also runs parallel with increased force of contraction, 86Rb+-uptake, however, is only inhibited at toxic glycoside concentrations. Thus, in rat and guinea pig heart there exist at least two different digitalis receptors--the high affinity receptor seems to be coupled to inotropic effects, the low affinity receptor is linked to inhibition of (Na+ + K+)-ATPase.

Animals↗
PubMed1984

Cardiac glycoside binding sites in cultured heart muscle cells.

Binding of (3H)-ouabain to cultured cardiac muscle and non muscle cells from chicken embryos and neonatal rats has been characterized and correlated with ouabain-induced inhibition of the sodium pump, as well as with the positive inotropic action of the drug. Cardiac muscle and non muscle cells from 10-12 day-old chicken embryos are characterized by a single class of ouabain binding sites (muscle cells: dissociation constant KD = 1.5 X 10(-7) M; binding capacity B = 2.6 pmoles/mg cell protein). Two classes of ouabain binding sites, however, have been found in cardiac muscle and non muscle cells from 1-3 day-old, neonatal rats (muscle cells: high affinity, low capacity sites: KD = 3.2 X 10(-8) M, B = 0.2 pmoles/mg protein; low affinity, high capacity sites: KD = 1.7 X 10(-6) M, B = 2.6 pmoles/mg protein). Half maximal inhibition of active (86Rb+ + K+)-influx occurs at 5.8 X 10(-7)M ouabain in chicken heart muscle cells and at 1.3 X 10(-5)M in rat heart muscle cells [( K+] = 0,75 mM). Decreases in cell-K+ (EC50 = 6.7 X 10(-7)M and 1.9 X 10(-5)M) and increases in cell-Na+ (7.4 X 10(-7) and 10(-5) - 10(-4)M) parallel ouabain-induced inhibition of the sodium pump. Up to 10(-6)M, ouabain does not affect velocity of cell wall motion in cultured rat heart muscle cells. A concentration-dependent increase in cell wall motion is observed at concentrations between 5 X 10(-6) and 5 X 10(-5)M, being indicative of a positive inotropic effect. At 10(-4)M ouabain, arrhythmias are present. Our data demonstrate the existence of one single class of cardiac glycoside receptors in cultured cardiac muscle cells from chicken embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Two binding sites for ouabain in cardiac cell membranes.

Cardiac glycoside receptors were defined by simultaneous measurement of 3H-ouabain binding and its effects on cardiac cell membranes, contracting cardiac muscle and cultured cardiac cells. These measurements show that: Rat and guinea pig cardiac cell membranes have two specific ouabain binding sites. In both species, ouabain binding to the high affinity site on cell membranes correlates with the positive inotropic effect in contracting cardiac muscle. Inhibition of (Na+ + K+)-ATPase activity corresponds to binding to the low affinity site. This questions the hypothesis that (Na+ + K+)-ATPase inhibition is necessary for ouabain-induced positive inotropy. K+ may induce an heterogeneity in the ouabain binding sites of the digitalis-sensitive cat and human heart.

Animals↗
PubMed1984

Evidence for two kinetically and functionally different types of cardiac glycoside receptors in the heart.

Cardiac glycosides bind with high affinity to specific receptors in the heart. In cardiac cell membranes of most animal species and man, this glycoside-receptor binding is followed by a subsequent inhibition of the membrane-bound (Na+ + K+)-ATPase, the biochemical equivalent of the active Na+/K+-transport system. Most investigators, however, have been unable to find, as a consequence of the glycoside-(Na+ + K+)-ATPase interaction, an inhibited Na+ or K+ transport in intact cardiac tissue when using low but positive inotropic concentrations of cardiac glycosides. In electrically stimulated contracting rat or guinea pig cardiac muscle we determined two kinetically different 3H-ouabain binding sites. The high affinity/low capacity site is related to positive inotropy, whereas the low affinity/high capacity binding site is connected to an inhibition of the (Na+ + K+)-ATPase. Occupation of the low affinity sites with ouabain molecules was concomitant with an increased intracellular Na+ and loss of K+ as well as onset of arrhythmias. According to our experiments, there are at least two different types of ouabain binding sites, inhibition of the (Na+ + K+)-ATPase was not necessarily related to positive inotropy in rat and guinea pig heart.

Animals↗
PubMed1984

Exogenous factors influencing the human erythrocyte sodium-lithium countertransport system.

It has recently been found that the Na+-Li+ countertransport across the human erythrocyte membrane is increased in patients with essential hypertension. We investigated the influence of hypokalaemia, oral contraceptives, diabetes mellitus and essential hypertension on the activity of this transport system. Normal values for the maximal Na+-Li+ transport rate were 0.25 +/- 0.08 mmol l-1 h-1 (males, n = 18) and 0.23 +/- 0.06 (females, n = 14). We found elevated values in women taking oral contraceptives (0.34 +/- 0.07, n = 10, P less than 0.001), in patients with chronic hypokalaemia due to diuretic or laxative abuse (0.41 +/- 0.16, n = 13, P less than 0.005) and in those with essential hypertension (0.32 +/- 0.08, n = 24, P less than 0.001) (all data mean +/- SD). Thus our results with hypertensive patients support the findings of other investigators. However, oral contraceptives and drug-induced hypokalaemia greatly modify this system, indicating a regulation of the Na+-Li+ countertransport by hormones. Thus the transport rate does not seem to be an appropriate test for the diagnosis of essential hypertension.

Adult↗
PubMed1984

Binding of digitalis derivatives to beef, cat and human cardiac (Na+ + K+)-ATPase. Affinity and kinetic constants.

We have measured the potency of 17 digitalis derivatives on cardiac (Na+ + K+)-ATPase from the digitalis-sensitive species, beef, cat and human. The potencies are given as the dissociation constant (KD-value) calculated from the concentration of unlabelled compound which inhibited 3H-ouabain binding by 50%, or from Scatchard or Woolf analyses. KD-values calculated by these independent methods were similar. As previously noted, structure-activity relationship (SAR) studies show that the binding of the whole molecule is necessary for optimal potency. The 3H-labelled derivatives of five of these compounds were used to measure the association and dissociation rate constants with cardiac (Na+ + K+)-ATPase. The rate constants for cat and human cardiac (Na+ + K+)-ATPase were very similar. Further, KD-values on cat and human cardiac (Na+ + K+)-ATPase for the 17 compounds tested showed a close correlation (r greater than 0.99), indicating that the cat heart is a suitable model for digitalis effects on the human heart.

Animals↗
PubMed1984

Comparison of the affinity of human, beef and cat heart (Na+ + K+)-ATPase for different digitalis derivatives.

The potencies of eight digitalis derivatives, including two new derivatives of digitoxin, were determined on heart (Na+ + K+)-ATPase or erythrocytes from three digitalis-sensitive species, beef, cat and human. Three methods were used: inhibition of 3H-ouabain binding to give the dissociation constant (KD-value), or inhibition of (Na+ + K+)-ATPase activity or 86Rb+-uptake into human erythrocytes to give the IC50-values. The same order of potency was observed with all methods. The slopes of the concentration-response curves were similar for all compounds. For all compounds, the concentrations which inhibited 3H-ouabain binding by 50% caused about a 50% inhibition of (Na+ + K+)-ATPase activity. All three methods are suitable for determining the potency of new semisynthetic digitalis derivatives. The two new derivatives of digitoxin, 3"'-dehydrodigitoxin oxime and 3"'-dehydrodigitoxin methyloxime, were less potent than digitoxin but were of similar potency to ouabain.

Animals↗
PubMed1984

[Extraction of a broken intracoronary PTCA guide wire perforating the circumflex artery, using a Dotter retrieval catheter].

Coronary artery perforation is a rare but potentially lethal complication during percutaneous transluminal coronary angioplasty (PTCA). To avoid pericardial tamponade, it has been suggested that perforating wires or balloons should not be withdrawn and that the patient should be transferred immediately to surgery. We report a case with a perforating and broken intracoronary guide wire which was successfully extracted using a Dotter intravascular retriever catheter. The only consequence was a small pericardial effusion not requiring pericardial puncture. Thus, emergency surgery is not inevitable after coronary artery perforation caused by thin intracoronary guide wires.

Angioplasty, Balloon↗
PubMed1984

A comparison of the effects of ouabain, dihydroouabain and 3 alpha-methyldigitoxigenin glucoside on guinea pig left atria.

The effects of ouabain, dihydroouabain and 3 alpha-methyldigitoxigenin glucoside on force of contraction and 86Rb+-uptake were measured in contracting guinea pig left atria. Dihydroouabain and 3 alpha-methyldigitoxigenin glucoside were both about 40 times less potent than ouabain. All compounds gave approximately the same maximal increase in force of contraction. The results gave no evidence that either dihydroouabain or 3 alpha-methyldigitoxigenin glucoside has a greater therapeutic index than ouabain. All compounds showed similar effect on 86Rb+-uptake (no significant change at positive inotropic concentrations, significantly decreased 86Rb+-uptake only at toxic concentrations). These results imply that these three compounds have a similar mechanism of action.

Animals↗
PubMed1983

Binding of dihydrodigitoxin to beef and human cardiac (Na+ + K+)-ATPase: evidence for two binding sites in cell membranes.

The specific binding of three cardiac glycosides, 3H-ouabain, 3H-digitoxin and 3H-dihydrodigitoxin, to beef cardiac (Na+ + K+)-ATPase was compared. Non-specific binding was defined as that in the presence of 0.1 mM unlabelled compound, or in the absence of ligands. The dissociation constants (KD-values) calculated from the inhibition of 3H-ouabain binding were: ouabain, 2.9 X 10(-9)M; digitoxin, 1.1 X 10(-9)M; and dihydrodigitoxin 2.7 X 10(-8)M. The concentrations which inhibited beef cardiac (Na+ + K+)-ATPase by 50% were: ouabain, 5.9 X 10(-9)M; digitoxin, 1.6 X 10(-9)M; and dihydrodigitoxin, 2.5 X 10(-8)M. Ouabain and digitoxin showed straight Scatchard plots for one site of high affinity (ouabain, KD = 2.6 X 10(-9)M; digitoxin, KD = 1.7 X 10(-9)M). However, dihydrodigitoxin gave a curved Scatchard plot. Analysis of this binding by the methods of M. J. Weidemann, H. Erdelt and M. Klingenberger (Eur. J. Biochem. 16, 313 (1970) for two binding sites gave the following results: for Mg2+,Pi-supported binding, the KD of the high affinity site was 1.6 X 10(-8)M with a capacity similar to that for ouabain of about 30 pmole/mg protein. For binding supported by Na+,ATP,Mg2+, the KD-value of the high affinity site was 5.3 X 10(-8)M of similar capacity. The low affinity binding site (KD = 4.0 X 10(-6)M for Mg2+,Pi; KD = 5.5 X 10(-6)M for Na+,ATP,Mg2+) bound about 350 pmole/mg protein. The low affinity site but not the high affinity site was also present in heat-denatured enzyme. Binding supported by Mg2+,Pi showed one low affinity site only for ouabain and dihydrodigitoxin in the presence of 200 mM Na+. The high affinity sites for these three cardiac glycosides were further characterized by measurement of the association and dissociation rate constants. The specific binding of 3H-ouabain and 3H-dihydrodigitoxin to human cardiac (Na+ + K+)-ATPase was measured. 3H-Ouabain showed a straight Scatchard plot for one high affinity site only (KD = 4.5 X 10(-9) M, capacity about 15 pmole/mg protein). 3H-Dihydrodigitoxin gave two binding sites: a high affinity site (KD = 1.8 X 10(-8) M) of similar capacity to ouabain, and a low affinity site (KD = 2.0 X 10(-6) M) of about 10-fold greater capacity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Digitalis structure-activity relationship analyses. Conclusions from indirect binding studies with cardiac (Na+ + K+)-ATPase.

We have performed direct and indirect binding studies with [3H]ouabain or [3H]digitoxin on beef or guinea pig cardiac (Na+ + K+)-ATPase to measure the potencies of a broad range of cardiotonic steroids for structure-activity relationship (SAR) studies for comparison with previously determined positive inotropic potencies. The positive inotropic potencies of twelve compounds on contracting guinea pig left atria correlated well with the equilibrium dissociation constants (KD values) from the inhibition of [3H]ouabain binding to guinea pig cardiac (Na+ + K+)-ATPase (r = 0.98 for seven 5 beta-compounds, r = 0.95 for five 5 alpha-compounds). Further we calculated KD values from the inhibition of [3H]ouabain binding data for a total of 33 digitalis derivatives on the digitalis-sensitive beef cardiac (Na+ + K+)-ATPase. For the 27 compounds tested on both beef cardiac (Na+ + K+)-ATPase and guinea pig left atria, the potencies showed a significant correlation (r = 0.92 for 22 5 beta-compounds, r = 0.96 for five 5 alpha-compounds. For seven compounds, KD values were measured on beef cardiac (Na+ + K+)-ATPase using inhibition of binding of [3H]digitoxin. These values correlated well (r = 0.99) with the KD values from the [3H]ouabain studies. These results show that: (1) The significant correlation observed between KD values on guinea pig cardiac (Na+ + K+)-ATPase and positive inotropic potency in guinea pig left atria is further evidence that the pharmacological receptor for inotropy is part of the enzyme, (2) Inhibition of the binding of [3H]ouabain or [3H]digitoxin can be used to determine the relative potencies of unlabelled digitalis derivatives. The similar relative potencies on beef and guinea pig cardiac (Na+ + K+)-ATPase of a broad range of digitalis derivatives indicate that the binding site is similar for both species; and (3) SAR studies indicate that functional groups on these steroids have the same influence on potency on either the positive inotropy or cardiac (Na+ + K+)-ATPase studies.

Animals↗
PubMed1983

Consequences of specific [3H]ouabain binding to guinea pig left atria and cardiac cell membranes.

An analysis of [3H]ouabain binding to electrically stimulated, contracting guinea pig left atria gave the following results. (1) A non-linear Scatchard plot with at least two binding sites: a high-affinity site (KD 1.1 X 10(-6) M) with about 430 receptors/micron2 related to positive inotropy, and a low-affinity site (KD' 2.1 X 10(-4) M) with about 18,000 receptors/micron2, possibly related to (Na+ + K+)ATPase inhibition. A crude left atrial homogenate gave about 530 receptors/micron2. (2) Half-maximal positive inotropic effects occurred at about 4 X 10(-7) M. (3) 86Rb+-uptake was significantly increased at all inotropic ouabain concentrations (10(-7) - 10(-6) M). Toxic concentrations (above 2 X 10(-6) M) inhibited 86Rb+-uptake (half-maximal inhibition at about 5 X 10(-6) M). [3H]Ouabain binding to partly purified guinea pig cardiac cell membranes showed: (a) linear Scatchard plots for (Mg2+, Pi)- and (Na+, ATP, Mg2+)-supported binding (KD 1.18 X 10(-7) M and 1.49 X 10(-7) M, respectively); (b) non-linear Scatchard plots for (Tyrode + ATP)-supported binding (KD 4.7 X 10(-7) M; KD' 6 X 10(-6) M); and (c) half-maximal [3H]ouabain binding occurred at a lower concentration (about 3.2 X 10(-7) M) than half-maximal inhibition of (Na+ + K+)ATPase activity (about 7.2 X 10(-7) M). Thus, we conclude that there may be more than one type of ouabain binding site in guinea pig left atria, and that measurable inhibition of (Na+ + K+)ATPase is not necessarily related to positive inotropy in the guinea pig.

Animals↗
PubMed1983

The cardiac glycoside-receptor system in the human heart.

Specific binding sites have been demonstrated to exist in the heart for several drugs and hormones such as beta-blocking agents, cardiac glycosides, catecholamines, insulin, glucagon and acetylcholine. The specific binding sites for cardiac glycosides in the human heart have certain properties which make it likely that they are the pharmacological receptors for the therapeutic and toxic actions of digitalis glycosides: they are located in the cell membrane and bind cardioactive steroids reversibly with high affinity: half-maximal receptor binding occurs at approximately 2 nM (approximately 1.5 ng/ml) for digoxin; potassium decreases receptor affinity, calcium increases it; specific binding of ouabain, digoxin or digitoxin is related to inhibition of (Na+ + K+)-ATPase activity--which is supposed to be the receptor enzyme for cardiac glycosides. Human left ventricle contains approximately 1.5 x 10(14) binding sites/g wet weight, right ventricle approximately 0.9 x 10(14). In disease the number of receptors may decrease (hypothyroid states, myocardial infarction) or increase (hyperthyroidism, chronic hypokalaemia). Certain drugs (such as phenytoin) or different temperatures or pH changes cause a change in digitalis-receptor affinity. Thus, the number of receptors and possibly their properties are subject to regulation in clinically relevant situations. Further investigations will probably reveal those pathophysiological states, which allow the explanation of toxicity or digitalis refractoriness.

Animals↗