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Biomedical subjects

K Werdan

Publications and source records attributed to K Werdan.

At least 163 records · Page 9Linked to original sources
PubMed1986

The red blood cell: a model for ouabain receptor regulation in the heart?

The assumption that the red blood cell can be used as a model for ouabain receptor regulation in heart muscle has been tested using isolated tissues from humans, guinea pigs, and chickens. The following results were obtained: The affinity of the ouabain receptor was similar in both human erythrocytes and right atrial appendage, but the density of binding sites was much lower on the erythrocytes. There was no correlation between the binding capacity in both tissues. Ouabain receptor occupation was closely correlated with inhibition of Na+/K+-transport in human erythrocytes and chick heart nonmuscle cells in culture. In contrast, in chick heart muscle cells, an occupation of 40% of the receptors decreased the Na+/K+-transport rate by only 10%. In hypokalemia, the ouabain binding capacity was increased in human and guinea pig erythrocytes but not in guinea pig heart muscle. Such increases were seen in chick heart nonmuscle cells in moderate hypokalemia but in heart muscle cells only after severe hypokalemia. Incubation of chick heart muscle cells in toxic but not in "therapeutic" ouabain concentrations increased the number of ouabain receptors. Increases in receptor number attenuated the positive inotropic and toxic actions of ouabain. These variations between ouabain receptor regulation in red blood cells and heart muscle of several species may be attributable to the lack of a "sodium pump reserve" in erythrocytes and heart nonmuscle cells. Such variations indicate that the human erythrocyte is not a suitable model for the ouabain receptor in the human heart.

Adolescent↗
PubMed1986

[Intracoronary nifedipine--separation of drug specific and vehicle-induced effects].

In 22 patients we studied the effects of 0.2 mg nifedipine given intracoronary during the course of routine PTCA. In 9 patients the effect of the nifedipine-free solvent was additionally tested. Injections were made through the guiding catheters or balloon catheters as pre- and poststenotic injections. We monitored frequency and character of pain, ECG changes (continuous recording of full 12-lead ECG) and pressure recordings from the left ventricle and pre- and poststenotic coronary artery. Short-lasting "stinging" pain sensations were described by 41% of the patients after nifedipine and 33% after solvent injection (n.s.). Patients described the pain as different from their usual angina pectoris. Pain was more frequent after poststenotic injections (through the balloon catheter) than after pre-stenotic injections (59% vs. 19%, p less than 0.01). ECG changes were peaking T waves, ST elevation and ST depression. They were recorded after pre-stenotic injections in 21 of 22 cases for nifedipine and 6 of 9 for solvent and after poststenotic injections in 22 of 22 cases for nifedipine and 8 of 9 cases for solvent. After nifedipine 0.2 mg i.c. the pressures decreased by 3.5% pre-stenotic and 9.7% post-stenotic. LVEDP increased by 10.7%. Our results show that pain sensations and electrocardiographic changes occur with similar character and frequency after i.c. injections of nifedipine or nifedipine-free solvent. Thus these effects do not seem to be caused by nifedipine. Hemodynamic effects were small and there was no disproportionate decrease of poststenotic pressure.

Angioplasty, Balloon↗
PubMed1985

Cardiac glycoside tolerance in cultured chicken heart muscle cells--a dose-dependent phenomenon.

In cultured heart muscle cells from 10-13 day-old chicken embryos, the effects of acute (4 h) and chronic (3 days) exposure of the cells to varying concentrations of ouabain have been studied. In these cells, the cardiac glycoside ouabain binds to a specific cardiac glycoside receptor (KD = 4 X 10(-7) M; 750,000 receptors/cell). Binding to this receptor results in inhibition of active Na+/K+-transport [EC50 for active (86Rb+ + K+)-influx = 4 X 10(-6) M], and in an increase in beating velocity ("positive inotropic effect"; EC50 = 4 X 10(-7) M); toxic signs (arrhythmias) appear at concentrations greater than or equal to 6 X 10(-7) M. During exposure of the cells to 3 X 10(-6) M ouabain for 3 days, tolerance develops with respect to both the positive inotropic and the toxic effect. The mechanism underlying this tolerance is identified as an increase in the number of active sodium pump molecules per cell, while the binding properties of the cardiac glycoside receptor remain unchanged. The development of cardiac glycoside tolerance is only observed in the presence of severe impairment of Na+/K+-homeostasis, due to cardiac glycoside-induced inhibition of active Na+/K+-transport. This, however, only occurs in the presence of toxic (receptor occupation greater than or equal to 60%), but not in the presence of positive inotropic, non-toxic (receptor occupation 20-60%), ouabain concentrations. We conclude that the development of cardiac glycoside tolerance during long-term treatment in patients with heart failure should not occur with submaximal dose regimens, when toxic signs (arrhythmias) are absent.

Animals↗
PubMed1984

Cardiac glycoside receptors in cultured heart cells--II. Characterization of a high affinity and a low affinity binding site in heart muscle cells from neonatal rats.

The binding of [3H]ouabain has been studied in (Na+ + K+)-ATPase enriched cardiac cell membranes, as well as in cardiac muscle and non-muscle cells in culture--all obtained from hearts of neonatal rats. The binding has been correlated with ouabain-induced inhibition of (Na+ + K+)-ATPase (cardiac cell membranes) and the inhibition of active (86Rb+ + K+)-influx (cardiac muscle and non-muscle cells in culture). Furthermore, the effect of ouabain on the amplitude of cell-wall motion and contraction velocity has been studied in electrically driven cardiac muscle cells. In muscle and non-muscle cells, two classes of ouabain binding sites have been identified. In rat heart muscle cells, the high affinity binding site has a dissociation constant (KD) of 3.2 X 10(-8) M and a binding capacity (B) of 0.2 pmole/mg protein (80,000 sites/cell); the values for the low affinity binding site are: KD = 7.1 X 10(-6) M; B = 2.6 pmole/mg protein (10(6) sites/cell). The binding to both types of binding sites is depressed by K+ and abolished after heat denaturation of the cells. The kinetics of [3H]ouabain binding to rat heart muscle cells (association and dissociation rate constants, K+- and temperature-dependence of association and dissociation processes) have been characterized. In rat heart muscle and non-muscle cells, the binding of [3H]ouabain to the low affinity site results in inhibition of the (86Rb+ + K+)-influx (EC50 = 1.3 and 1.5 X 10(-5) M ouabain), a decrease in cell-K+ (EC50 = 1.9 and 1.4 X 10(-5) M) and an increase in cell-Na+ (10(-5)-10(-4) M). The ouabain-induced positive inotropic effect (increase in amplitude of cell-wall motion, increase in contraction velocity) in cardiac muscle cells is observed only at ouabain concentrations greater than or equal to 5 X 10(-6) M, and it is therefore probably attributed to occupation of the low affinity binding site. Coupling of occupation of the low affinity site by ouabain with drug-induced inhibition of the sodium pump and with drug-induced positive inotropic action is further substantiated by kinetic measurements. In contrast, occupation of the high affinity binding site does not produce any measurable inhibition of the sodium pump activity or positive inotropy.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Influence of digitalis and diuretics on ouabain binding sites on human erythrocytes.

It has been reported that during chronic treatment with digitalis, the number of digitalis binding sites is increased in human erythrocytes [22]. From this finding a tachyphylaxis for cardiac glycosides has been postulated. We reinvestigated this problem in several groups of patients. The number of 3H-ouabain binding sites per erythrocyte in control persons (group I) was 214 +/- 60, n = 43 (means +/- SD). The dissociation constant (KD) was 1.8 +/- 0.5 nM. Thirteen patients (group II) taking cardiac glycosides only, for at least 6 months, had 281 +/- 99 (p less than 0.05) ouabain binding sites per single red cell, KD = 1.8 +/- 0.7 nM. Group III (34 patients) took digitalis for more than 6 months and diuretics for at least 3 months (352 +/- 126 (p less than 0.001), KD = 1.6 +/- 0.6). Twenty-three of these (group IV) were taking a combination with "K+-saving" diuretics (336 +/- 194 (p less than 0.01), KD = 1.6 +/- 0.5) and (group V, 11 patients) a combination with "K+-losing" diuretics (462 +/- 133 (p less than 0.001), KD = 1.4 +/- 0.4). Nine patients (group VI) had a chronic hypokalemia, mainly due to taking furosemide (437 +/- 98 (p less than 0.001), KD = 1.5 +/- 0.4). Four control persons took 50 mg hydrochlorothiazide daily for more than 4 months without measurable K+-losses and without changes in ouabain binding sites. It is concluded from these findings that diuretic treatment with chronic hypokalemia in addition to digitalis is accompanied by a significant increase in ouabain binding sites in human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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

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↗