Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The search for endogenous digitalis led to the isolation of ouabain from blood adrenals and hypothalamus. Additional cardiotonic steroids of the cardenolid and bufadienolide type seem to circulate in blood. Adrenal cortical cells in tissue culture release ouabain upon addition of angiotensin 11. Ouabain in blood is increased in 50% of Caucasians with low renin hypertension. Analogous to other steroid hormones, cardiotonic steroid hormones in blood are bound to a specific cardiac glycoside binding globulin. Since ouabain induced growth of myocytes in tissue culture, this effect probably mediates by partial inhibition of the sodium pump and consecutive rise of intracellular Ca2+ the thickening of the wall of arteries and myocardium. PST 2238, an antagonist of cardiac glycoside function at the sodium pump, leads in rats under prolonged therapy to a decrease of hypertension. The finding of ouabain as a new adrenal hormone of the Na+ metabolism and of ouabain antagonists opens new possibilities of therapy of hypertension and congestive heart failure.
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PMID:Endogenous cardiotonic steroids. 1135 1

Ouabain increases vascular resistance and may induce hypertension by inhibiting the Na+ pump. The effects of 0.18 and 18 microg/kg, and 1.8 mg/kg ouabain pretreatment on the phenylephrine (PHE; 0.1, 0.25 and 0.5 microg, in bolus)-evoked pressor responses were investigated using anesthetized normotensive (control and uninephrectomized) and hypertensive (1K1C and DOCA-salt treated) rats. Treatment with 18 microg/kg ouabain increased systolic and diastolic blood pressure in all groups studied. However, the magnitude of this increase was larger for the hypertensive 1K1C and DOCA-salt rats than for normotensive animals, while the pressor effect of 0.18 microg/kg ouabain was greater only in DOCA-salt rats. A very large dose (1.8 mg/kg) produced toxic effects on the normotensive control but not on uninephrectomized or 1K1C rats. Rat tail vascular beds were perfused to analyze the effects of 10 nM ouabain on the pressor response to PHE. In all animals, 10 nM ouabain increased the PHE pressor response, but this increase was larger in hypertensive DOCA-salt rats than in normotensive and 1K1C rats. Results suggested that a) increases in diastolic blood pressure induced by 18 microg/kg ouabain were larger in hypertensive than normotensive rats; b) in DOCA-salt rats, smaller ouabain doses had a stronger effect than in other groups; c) hypertensive and uninephrectomized rats were less sensitive to toxic doses of ouabain, and d) after treatment with 10 nM ouabain isolated tail vascular beds from DOCA-salt rats were more sensitive to the pressor effect of PHE than those from normotensive and 1K1C hypertensive rats. These data suggest that very small doses of ouabain, which might produce nanomolar plasma concentrations, enhance pressor reactivity in DOCA-salt hypertensive rats, supporting the idea that endogenous ouabain may contribute to the increase and maintenance of vascular tone in hypertension.
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PMID:Effects of small doses of ouabain on the arterial blood pressure of anesthetized hypertensive and normotensive rats. 1147 Oct 47

Ouabain has recently been identified as an endogenous Na+-K+ pump inhibitor having a close association with hypertension. However, some patients with hypertention do not show high levels of endogenous ouabain (EO), and patients with high EO levels do not necessarily suffer from hypertention. It is believed that the Na+-K+-ATPase activity in essential hypertension does not undergo homogenous change. The present study was designed, therefore, to investigate the expression and the significance of the Na+-K+-ATPase alpha-subunit isoforms in kidney tissue in ouabain-hypertensive rats. Ouabain was administered chronically to establish a model of ouabain-hypertensive rats. Biochemical analysis, cytobiology and sABC immunohistochemistry were they used to assay for expression of Na+-K+-ATPase alpha-subunit isoforms in kidney tissue. After the first week of receiving ouabain, 65% (n=13) of rats had hypertension. After the second week, the blood pressure of these 13 hypertensive rats was increased significantly compared to the baseline and control levels (p<0.05). The plasma renin activity was normal, and angiotensin II and aldosterone levels were increased significantly in these rats (p<0.05). But in the other 35% (n=7) of rats of the experimental group, there was no apparent increase in blood pressure after receiving ouabain. The plasma ouabain level in the non-hypertensive subgroup was significantly higher than that in the hypertensive subgroup, but the 86Rb intake and the number of 3H-ouabain binding sites did not decrease. The Na+-K+-ATPase activity showed non-homogeneous changes. In hypertensive rats, the expression levels of ouabain paralleled the degree of hypertension (r=0.88, p<0.05). The positive granules were mainly scattered in the cytoblastoma of the reticular zone of adrenal cortex. There were thus different levels of expression of Na+-K+-ATPase alpha-subunit isoforms in this model. In the hypertension subgroup the alpha1 was most strongly expressed, followed by the alpha2 and alpha3 isforms. But in the non-hypertensive subgroup the order was alpha3 > alpha2 > alpha1. The positive granular was mainly scattered in the convoluted tubules of the kidney. These results suggest that the high level of ouabain and the change of the Na+-K+-ATPase alpha-subunit isoforms may play a critical role in hypertension.
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PMID:The change and significance of the Na+-K+-ATPase alpha-subunit in ouabain-hypertensive rats. 1176 35

Hypertension development, phenylephrine-induced contraction and Na(+),K(+)-ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain- (25 microg day(-1), s.c., 5 weeks) and vehicle-treated rats were evaluated. Ouabain treatment increased systolic blood pressure (127+/-1 vs 160+/-2 mmHg, n=24, 35; P<0.001) while the maximum response to phenylephrine was reduced (P<0.01) in AO (102.8+/-3.9 vs 67.1+/-10.1% of KCl response, n=12, 9) and SMA (82.5+/-7.5 vs 52.2+/-5.8%, n=12, 9). Endothelium removal potentiated the phenylephrine response to a greater extent in segments from ouabain-treated rats. Thus, differences of area under the concentration-response curves (dAUC) in endothelium-denuded and intact segments for control and ouabain-treated rats were, respectively: AO, 56.6+/-9.6 vs 198.3+/-18.3 (n=9, 7); SMA, 85.5+/-15.4 vs 165.4+/-24.8 (n=6, 6); TA, 13.0+/-6.1 vs 39.5+/-10.4% of the corresponding control AUC (n=6, 6); P<0.05. The relaxation to KCl (1 - 10 mM) was similar in segments from both groups. Compared to controls, the inhibition of 0.1 mM ouabain on KCl relaxation was greater in AO (dAUC: 64.8+/-4.6 vs 84.0+/-5.1%, n=11, 14; P<0.05), similar in SMA (dAUC: 39.1+/-3.9 vs 43.3+/-7.8%, n=6, 7; P>0.05) and smaller in TA (dAUC: 62.1+/-5.5 vs 41.4+/-8.2%, n=12, 13; P<0.05) in ouabain-treated rats. Protein expression of both alpha(1) and alpha(2) isoforms of Na(+),K(+)-ATPase was augmented in AO, unmodified in SMA and reduced in TA from ouabain-treated rats. These results suggest that chronic administration of ouabain induces hypertension and regional vascular alterations, the latter possibly as a consequence of the hypertension.
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PMID:Alterations in phenylephrine-induced contractions and the vascular expression of Na+,K+-ATPase in ouabain-induced hypertension. 1183 25

Sodium-potassium pumps (Na pumps) are the only known plasma membrane receptors for cardiac glycosides. However, adrenocortical cells secrete an endogenous ouabain via an unknown mechanism that is subject to feedback inhibition via the cell surface. In addition, recent studies suggest that the induction of sustained hypertension by ouabain analogs in rats may be independent of Na pump inhibition. Accordingly, we used bovine adrenocortical cells and membranes to search for novel binding sites for ouabain. In high extracellular potassium solutions, the binding of ouabain to the Na pumps of cultured cells was suppressed, yet residual specific binding of (3)H-ouabain was observed. In high extracellular potassium, Scatchard analyses revealed a novel class of ouabain binding sites with high affinity (<50 nmol/L, < 2.5 x 10(5) sites/cell) that was distinct from the low-affinity Na pump sites (>1 micromol/L, 4.5 x 10(6) sites/cell). Analysis of the kinetics for the dissociation of (3)H-ouabain from intact cells revealed components whose t(0.5) values were 6.5 minutes, 3.3 hours, and 33 hours and associated with novel sites, Na pumps, and lysosomal recycling, respectively. Studies with isolated membranes under ligand conditions where the participation of Na pumps was minimized revealed specific ouabain binding to novel sites that was saturable, time-dependent, of high affinity (K(d) approximately 15 nmol/L), and of low density (apparent B(max)=0.23 pmol/mg, c.f., Na pumps=10.2 pmol/mg). Ouabain binding to the novel sites was stimulated by high concentrations of KCl but was not affected by aldosterone or cortisol up to 30 micromol/L. Novel sites were not detected in skeletal muscle or liver membranes. Photoaffinity studies followed by SDS-PAGE showed ouabain-protectable labeling of membrane polypeptides with apparent molecular weights of 143, 113, and 65 kDa. We conclude that adrenocortical cells express ouabain receptors that are distinct from Na pumps. These novel receptors may be involved in the regulation and/or secretion of endogenous ouabain.
Hypertension 2002 Feb
PMID:Novel receptors for ouabain: studies in adrenocortical cells and membranes. 1188 4

The search for endogenous digitalis has led to the isolation of ouabain as well as several additional cardiotonic steroids of the cardenolide and bufadienolide type from blood, adrenals, and hypothalamus. The concentration of endogenous ouabain is elevated in blood upon increased Na(+) uptake, hypoxia, and physical exercise. Changes in blood levels of ouabain upon physical exercise occur rapidly. Adrenal cortical cells in tissue culture release ouabain upon addition of angiotensin II and epinephrine, and it is thought that ouabain is released from adrenal cortex in vivo. Ouabain levels in blood are elevated in 50% of Caucasians with low-renin hypertension. Infusion over several weeks of low concentrations of ouabain, but not of digoxin, induces hypertension in rats. A digoxin-like compound, which has been isolated from human urine and adrenals, as well various other endogenous cardiac glycosides may counterbalance their actions within a regulatory framework of water and salt metabolism. Marinobufagenin, for instance, whose concentration is increased after cardiac infarction, may show natriuretic properties because it inhibits the alpha1 isoform of Na(+)/K(+)-ATPase, the main sodium pump isoform of the kidney, much better than other sodium pump isoforms. In analogy to other steroid hormones, cardiotonic steroid hormones in blood are bound to a specific cardiac glycoside binding globulin. The discovery of ouabain as a new adrenal hormone affecting Na(+) metabolism and the development of the new ouabain antagonist PST 2238 allows for new possibilities for the therapy of hypertension and congestive heart failure. This will lead in turn to a better understanding of the disease on a physiological and endocrinological level and of the action of ouabain on the cellular level as a signal that is transduced to the plasma membrane as well as to the cell nucleus.
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PMID:Endogenous cardiac glycosides, a new class of steroid hormones. 1202 81

Conservation of the binding site on mammalian Na+,K+-ATPase for cardiac glycosides and the importance of the Na+ pump in mammalian cellular physiology has stimulated the search for a mammalian analog of these plant compounds. One candidate, isolated from brain and blood, appears to be ouabain itself or a closely related isomer, the ouabain-like compound. Little is known about the circulating form. Because human steroid hormones circulate with carrier proteins, we produced a ouabain-specific monoclonal antibody (mAb 1-10) and used it to probe normal human plasma for ouabain-protein carrier complex. Ouabain-like biological activity was isolated in association with protein bands of 80, 50, and 25 kDa. These proteins appear to be human immunoglobulins or immunoglobulin-like because they are recognized by anti-human immunoglobulin antibodies, but not by anti-mouse immunoglobulin antibodies. The protein-containing fractions inhibit the binding of mAb 1-10 to immobilized ouabain, and with further purification on protein A, the immunoglobulin-like protein binds radioactive ouabain with an IC50 of 200 to 600 nmol/L, but binds digoxin with 100-fold less affinity, suggesting specificity for ouabain or its isomer. Active protein fractions after purification on C18 inhibit Na+ pump activity in human erythrocytes (IC50 approximately 4 nmol/L, ouabain equivalents), and this chromatography appears to dissociate the ouabain-like compound from the immunoglobulin protein(s). These immunoglobulin-like molecules may represent a subset of immunoglobulins (< or =0.5% of total protein A immunoglobulin) that function as a reservoir and delivery system for ouabain-like compounds in the modulation of human Na+, K+-ATPase in vivo.
Hypertension 2002 Aug
PMID:Ouabain-binding protein(s) from human plasma. 1215 17

The erythrocytes are widely used as model cells for studies of sodium-potassium pump (Na(+)-K(+) pump) in health and disease. Hence, to explore the possible role of the Na(+) transport across the cell membrane in the pathogenesis of pregnancy-induced hypertension (PIH), the present study was conducted to assess the Na(+)-K(+) pump functions in relation to its intrinsic kinetic properties using erythrocytes (RBC). Erythrocyte sodium concentration in pregnancy-induced hypertensive women was significantly (p<0.01) lower in comparison to normotensive pregnant women. On the contrary erythrocyte potassium was significantly higher (p<0.01) in PIH women as compared to normotensive pregnant women. Observed alterations in Na(+) and K(+) concentrations in erythrocytes were associated with significantly (p<001) increased Ouabain-sensitive sodium efflux rate and rate constants in erythrocytes from PIH women. Further, kinetic studies revealed that increased Ouabain-sensitive efflux rate constant in RBC from PIH women was accompanied by increased maximal velocity (V(max)) of Na(+)-K(+) pump. However, the affinity constant (K(m)) was unaltered in both the groups. Therefore, these findings suggest that increased Na(+)-K(+) pump activity in RBC of PIH women could be due to either increased numbers of Na(+)-K(+) pump units of increased numbers of active subunits of Na(+)-K(+) pump possibly due to specific plasma factors in PIH women.
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PMID:Alteration in ouabain-sensitive sodium potassium pump of erythrocytes during pregnancy induced hypertension: a kinetic study. 1218 49

Ouabain is an endogenous compound that has been associated with the genesis and maintenance of hypertension. This compound inhibits the Na+ pump activity, which leads to an accumulation of intracellular Na and ultimately might increase vascular tone. In nanomolar concentrations, it enhances vasopressor responses to phenylephrine in some vascular beds from normotensive and hypertensive rats. However, it is not known whether this action of ouabain is a common mechanism for all models of hypertension. The aim of this work was to determine whether ouabain can alter pressor responses to phenylephrine in rats with Nomega-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. In anesthetized rats, ouabain (0.18 microg/kg, i.v.) increased arterial blood pressure in L-NAME-treated rats but not in controls. Ganglionic blockade by hexamethonium (5 mg/kg, i.v.) prevented the increase in arterial blood pressure produced by ouabain in L-NAME-treated rats. Additional studies using isolated perfused tail artery preparations were performed to investigate which factors are involved in the action of ouabain in L-NAME-treated rats. The effects of 10 nM ouabain on the vasoconstrictor actions of phenylephrine were determined on preparations with intact or damaged endothelium or in the presence of tetraethylammonium (a K+-channel blocker). Ouabain reduced pressor actions of phenylephrine in preparations with an intact endothelium. However, after endothelial damage or infusing tetraethylammonium, the response to phenylephrine was increased after ouabain. In tails from L-NAME-treated rats, the functional activity of the Na, K+-ATPase was reduced, and 10 nM ouabain did not produce any further reduction. In conclusion, in this model of hypertension, a low dose of ouabain (0.18 microg/kg) increased arterial blood pressure in vivo probably as a result of increased sympathetic tone. However, this effect was not accompanied by an enhanced action of phenylephrine on the tail vascular bed with an intact endothelium. The results suggest that this was due to the release of an endothelium-derived K+-channel opener.
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PMID:Ouabain changes arterial blood pressure and vascular reactivity to phenylephrine in L-NAME-induced hypertension. 1250 28

Immune dysfunction has been reported in hypertensive rats, and circulating levels of ouabain are increased in some experimental models of hypertension. Ouabain is an inhibitor of the Na+/K+-ATPase capable of diverse effects on cells of the immune system, but its mode of action on these cells is still unknown. The levels of cytoplasmic calcium ions play an important role in cell signaling, and ouabain may induce an increase in intracellular calcium indirectly through the Na+/Ca2+ exchanger. The current work examined the possibility that this drug could be exerting its effects on thymocytes through calcium mobilization and an increase in the cytosolic calcium concentration. Intracellular calcium was evaluated by using Balb-c mouse thymocytes loaded with FURA-2. Both intracellular and extracellular calcium pools were mobilized by ouabain (3 to 1000 nmol). The influx of extracellular calcium depended on the Na+/Ca2+ exchanger and on voltage-dependent calcium channels, as it was inhibited by amiloride and benzamil, consistent with the inhibition of the Na+/K+ pump. In addition, the increase of calcium from intracellular stores was extremely rapid. Furthermore, an increase in cytosolic calcium levels was obtained with the combination of ouabain and thapsigargin, which was greater than that seen with either drug alone. Our data suggest that low concentrations of ouabain may be acting on thymocytes through a mechanism different from the traditional inhibition of the Na+/K+-ATPase, as the cytosolic calcium rise was partly dependent on the release from intracellular stores.
Hypertension 2003 Jun
PMID:Ca2+ mobilization induced by ouabain in thymocytes involves intracellular and extracellular Ca2+ pools. 1273 88


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