The cardiac glycoside-receptor system in the human heart

Erdmann, E; Brown, Lindsay

doi:10.1093/eurheartj/4.suppl_a.61

Cited by 27 publications

(7 citation statements)

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“…The number of binding sites is decreased by 50 %. This might be a reflection of membrane disappearance, following membrane disruption and cell lysis, as has been explained for the decrease in ouabain binding sites observed in the area of lesion after myocardial infarction (7). Hypertrophy is also associated with acute rejection, and results in lower binding sites capacity and may explain our results.…”

Section: Discussionsupporting

confidence: 63%

“…Pathological states have also been shown to modify digitalis receptor properties. A significant decrease in the number of cardiac ouabain binding sites has been observed in senescent rats, hypothyroid states, myocardial infarction, in an experimental model of hypertension and in diabetic cardiomyopathy (7,9,13,15,19). Indeed, both affinity and binding capacity of low affinity ouabain binding sites were decreased in cardiac hypertrophy (3).…”

Section: Discussionmentioning

confidence: 99%

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Decreased digitalis receptor activity in acute rejecting canine transplanted heart

1987

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In the course of acute rejection, myocardial tissue undergoes massive transformation and we hypothetized that for digitalis-like substances, receptor binding characteristics might be altered. Ten canine heterotopic cardiac allografts were carried out and were harvested once rejection had developed (8-10 days post-transplant). Microsomal membrane fractions of those grafts and of native hearts were isolated. Radioligand binding studies were carried out in a medium containing 5 mM Tris PO4, 50 mM Tris HCl, 5 mM MgCl2, pH 7.4 at 37 degrees C, using 3H-ouabain as the ligand. Saturation experiments (n = 10) indicate the presence of one homogeneous population of high affinity binding sites with an affinity constant (Kd) of 8-13 nM and a maximum binding capacity (Bmax) of 47 +/- 3.5 pmol/mg protein. Both saturation and competition binding studies illustrate the fact that acute rejection resulted in a significant decrease in Bmax (43%) without significant alteration in Kd value. These studies indicate that digitalis-like substances might not exert significant inotropic activity during rejection, but this hypothesis must be confirmed by in vivo haemodynamic experiments.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Decreased digitalis receptor activity in acute rejecting canine transplanted heart

1987

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“…The differences in the ouabain binding kinetics of human Na,K-ATPase isozymes reported in this study may be reflected in studies on human cardiac plasma membranes where the rapid dissociation process described (t1 ⁄2 10 -13 min) (35,48) could correspond to ␣2-␤ complexes (t1 ⁄2 4 -5 min) while the slower process described (t1 ⁄2 39 -75 min) (35,48,49) could correspond to ␣1-␤ and/or ␣3-␤ isozymes (t1 ⁄2 30 -80 min). On the other hand, in human cardiac plasma membranes, only one association rate constant was described ranging from 0.12 ϫ 10 7 -0.7 ϫ 10 7 M Ϫ1 min Ϫ1 (35,49,50).…”

Section: Pharmacological Properties Of Human Nak-atpase Isozymesmentioning

confidence: 76%

“…On the other hand, in human cardiac plasma membranes, only one association rate constant was described ranging from 0.12 ϫ 10 7 -0.7 ϫ 10 7 M Ϫ1 min Ϫ1 (35,49,50). The particular features of ␣2 isozymes concerning the ouabain binding kinetics allow speculations on their pharmacological role during digitalis treatment.…”

Section: Pharmacological Properties Of Human Nak-atpase Isozymesmentioning

confidence: 99%

Transport and Pharmacological Properties of Nine Different Human Na,K-ATPase Isozymes

Crambert¹,

Hasler²,

Beggah³

et al. 2000

Journal of Biological Chemistry

397

378

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Na,K-ATPase plays a crucial role in cellular ion homeostasis and is the pharmacological receptor for digitalis in man. Nine different human Na,K-ATPase isozymes, composed of 3 ␣ and ␤ isoforms, were expressed in Xenopus oocytes and were analyzed for their transport and pharmacological properties. According to ouabain binding and K ؉ -activated pump current measurements, all human isozymes are functional but differ in their turnover rates depending on the ␣ isoform. On the other hand, variations in external K ؉ activation are determined by a cooperative interaction mechanism between ␣ and ␤ isoforms with ␣2-␤2 complexes having the lowest apparent K ؉ affinity. ␣ Isoforms influence the apparent internal Na ؉ affinity in the order ␣1 > ␣2 > ␣3 and the voltage dependence in the order ␣2 > ␣1 > ␣3. All human Na,K-ATPase isozymes have a similar, high affinity for ouabain. However, ␣2-␤ isozymes exhibit more rapid ouabain association as well as dissociation rate constants than ␣1-␤ and ␣3-␤ isozymes. Finally, isoformspecific differences exist in the K ؉ /ouabain antagonism which may protect ␣1 but not ␣2 or ␣3 from digitalis inhibition at physiological K ؉ levels. In conclusion, our study reveals several new functional characteristics of human Na,K-ATPase isozymes which help to better understand their role in ion homeostasis in different tissues and in digitalis action and toxicity.

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“…The density of ouabain binding sites varies markedly between different cell types with heart muscle containing about 1,000 binding sites/gin 2 [11], mononuclear leucocytes about 200 binding sites/gm 2 (about 35,000 sites/cell) [4] and erythrocytes about 1-2 binding sites/gm 2 (about 250 sites/ cell) [12]. Of these cells, only the erythrocyte does not possess a nucleus.…”

Section: Discussionmentioning

confidence: 99%

3H-ouabain binding to human mononuclear leucocytes

1985

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Specific binding of cardiac glycosides to intact human blood cells may be a suitable model for physiological or disease-induced changes in cardiac glycoside binding to human heart muscle. Since the erythrocyte contains no nucleus and has relatively few binding sites compared with heart muscle, intact mononuclear leucocytes were investigated in the present study. Using leucocyte suspensions from 34 normal subjects, 133 measurements of 3H-ouabain binding-were obtained. 3H-Ouabain bound to one type of binding site with an affinity (KD) of 2.8 +/- 1.2 X 10(-9) M, similar to that of human heart muscle. Association and dissociation were slow processes (k+1, 3.9 X 10(4) M-1 sec-1; k-1, 8.1 X 10(-5) sec-1, n = 2). The number of ouabain binding sites/leucocyte varied from 18,000 to 60,000 (mean +/- SD, 34,600 +/- 9,700), with no correlation with the proportion of monocytes present or with the serum K+-level of the donors. Large inter- and intra-individual differences in binding site number were measured which are probably a result of the heterogeneity of the cell suspension used. Thus, the ouabain binding site on human heart muscle and intact mononuclear leucocytes is probably identical. However, the number of binding sites in mixtures of mononuclear leucocytes shows large and inconsistent intraindividual variations, making these studies unsuitable for quantifying drug- or disease-induced changes in ouabain binding site number.

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The cardiac glycoside-receptor system in the human heart

Cited by 27 publications

References 0 publications

Decreased digitalis receptor activity in acute rejecting canine transplanted heart

Decreased digitalis receptor activity in acute rejecting canine transplanted heart

Transport and Pharmacological Properties of Nine Different Human Na,K-ATPase Isozymes

3H-ouabain binding to human mononuclear leucocytes

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