This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goto, A. Articles by Omata, M. Search for Related Content PubMed PubMed Citation Articles by Goto, A. Articles by Omata, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB OUABAIN

(Hypertension. 1996;28:421-425.)
© 1996 American Heart Association, Inc.

Articles

Ouabainlike Compound in Hypertension Associated With Ectopic Corticotropin Syndrome

Atsuo Goto; Kaoru Yamada; Hisanori Hazama; Yoshio Uehara; Keiichiro Atarashi; Yasunobu Hirata; Kenjiro Kimura; Masao Omata

the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, and Department of Human Dry Dock, Sanraku Hospital (K.Y.), Tokyo, Japan.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Molecular mechanisms related to sodium retention have been implicated in the pathogenesis of hypertension. It is unclear how sodium retention leads to a rise in blood pressure, but ouabainlike compound may act as a final common pathway in sodium-induced hypertension. In ectopic corticotropin syndrome, hypertension has been attributed to cortisol inactivation overload, giving rise to mineralocorticoid-type hypertension. We sequentially measured plasma and urinary levels of ouabainlike compound over 2 months to evaluate its role in the hypertensive mechanisms in a 64-year-old man with this syndrome caused by lung cancer. His data included hypokalemia and increased cortisol concentrations, corticotropin levels, and urinary 17-hydroxycorticosteroid excretion. Plasma renin activity was suppressed. Plasma and urinary levels of ouabainlike compound were markedly increased concomitantly with high blood pressure. The maximum plasma level was 40-fold the normal range of the subject. After chemotherapy, ouabainlike compound levels gradually decreased in parallel with the decline in blood pressure and rise in potassium concentration. A correlation was observed between plasma and urinary levels of ouabainlike compound (P<.05). Plasma and urinary levels of ouabainlike compound correlated with systolic (P<.01) and diastolic (P<.05) pressures, respectively. The peak of ouabainlike compound in plasma and urine coincided with that of authentic ouabain on high-performance liquid chromatography. Ouabainlike compound derived from urine inhibited [³H]ouabain binding to human erythrocytes. These findings suggest that ouabainlike compound with biological activity could partly account for hypertension in ectopic corticotropin syndrome.

Key Words: hormones • adrenocorticotropic hormone • Na⁺,K⁺-transporting ATPase • sodium-potassium pump • blood pressure • potassium • sodium

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Substantial progress has been made in elucidating the molecular mechanisms that cause several forms of hypertension, including Liddle's syndrome, glucocorticoid-suppressible aldosteronism, and the syndrome of apparent mineralocorticoid excess.^{1 2 3} Hypertension in these syndromes is related to sodium retention due to activated sodium channels, excessive aldosterone synthesis in the zona fasciculata, and deficient inactivation of cortisol, respectively. Sodium retention is also important in the pathogenesis of primary aldosteronism.^{4 5} However, it is unclear how sodium retention leads to the rise in BP.

Sodium pump inhibitors have been proposed to play a role in sodium metabolism, fluid balance, and cardiovascular function and may act as a final common pathway in sodium-induced hypertension.^{6 7 8 9 10} Recent studies provide evidence that a major biologically active sodium pump inhibitor in the circulation may be an isomer of ouabain (OLC) that is distinct from ouabain.^{11 12 13} Although there is still growing evidence of other potentially important sodium pump inhibitors that are obviously not OLC,^{14 15 16} OLC appears to fulfill many of the criteria required for a circulating sodium pump inhibitor. Although the natriuretic action of OLC is still controversial, its hypertensinogenic action in several types of hypertension has been suggested.^{17 18 19 20 21} In this report, we describe a patient with ectopic ACTH syndrome caused by lung cancer in which a role of circulating OLC has been suggested in mineralocorticoid-type hypertension produced by cortisol excess.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Protocol
The patient gave written informed consent, and the study protocol was approved by the Ethics Committee of the University of Tokyo. BP measurements were made at 6:30, 7, 7:30, and 8 AM with the patient fasting and before he had taken antihypertensive medications. The BP value during this time was selected to exclude the effects of drug as much as possible. Each time BP was measured three times with a sphygmomanometer after the patient had been supine for at least 15 minutes, and these values were averaged. Mean BP was calculated as diastolic BP plus one third pulse pressure.

Plasma samples for OLC were obtained at 8 AM on 23 different days over 2 months from September 3 to November 5 for examination of serial changes in OLC levels along with BP values and plasma electrolyte concentrations. Urine was simultaneously collected for OLC and electrolyte measurements over the 24 hours. Plasma and urinary OLC was measured by radioimmunoassay of ouabain using 1 mL of each sample as described previously¹⁷ with a slight modification. Antibody-bound ouabain was separated from free ouabain with a second antibody (sheep anti-rabbit IgG; UCB-Bioproducts SA) instead of dextran-coated charcoal and was counted by liquid scintillation. Because we eluted the OLC-containing fraction with 25% acetonitrile in water from a Sep-Pak C18 cartridge (Waters Associates), it is unlikely that our OLC levels, at least in plasma, included common adrenocortical steroids. These steroids are too hydrophobic to be eluted at this acetonitrile concentration. The antiserum showed minimum cross-reactivity with common steroids¹⁷ (cortisol, cortisone, deoxycorticosterone, testosterone, progesterone, prognenolone, dehydroepiandrosterone sulfate, and ß-estradiol; all <0.001%). Cross-reactivities of the antiserum with digoxin, gitoxin, and dihydro-ouabain were 4.1%, 0.01%, and 0.25%, respectively. Polar metabolites of corticosterone and cortisol such as 6ß-OH-corticosterone and 6ß-OH-cortisol have a polarity similar to that of ouabain, and our sample might contain these metabolites.¹⁶ However, our antibody did not cross-react with 6ß-OH-corticosterone and 6ß-OH-cortisol at the concentration of 10^-4 to 10^-10 mol/L (unpublished data, 1995). The mean plasma OLC value obtained from 30 healthy volunteers (mean age, 33 years) was 76±14 pmol/L.²² We compared plasma- and urine-derived OLC with authentic ouabain using 5 or 150 mL of pooled plasma or urine, respectively, obtained during 2 weeks after hospital admission on reversed-phase HPLC. The OLC-containing fraction from a Sep-Pak C18 cartridge was analyzed on an R-ODS-5 column (Yamamura Chemical Co) with a gradient of acetonitrile in water (0% to 30%) over 30 minutes after washing with water over 9 minutes at 1 mL/min. One-minute fractions were collected, freeze-dried, and assessed for ouabain immunoreactivity. To confirm the digitalis-like biological activity associated with urinary OLC, we used an inhibitory effect on [³H]ouabain binding to human erythrocytes according to the method described previously.²³ Electrolyte concentrations were measured by flame photometry. Correlation plots were obtained by the least-squares method. Data are given as mean±SE.

Case Report
A 64-year-old man presented with a 2-month history of productive cough. A chest radiograph and thoracic computed tomographic scan revealed an abnormal shadow in the right lung hilus. A transbronchial lung biopsy showed a typical small-cell cancer with metastasis to a hilar lymph node. Superior vena caval syndrome gradually occurred, and the patient was admitted to our hospital for chemotherapy on September 1, 1993.

Physical examinations showed a BP of 180/90 mm Hg, edema in the face and right upper extremity, and mild dyspnea. A chest radiograph on admission demonstrated mild cardiac enlargement, right pleural effusion, and atelectasis in the right lower lobe in addition to the abnormal shadow.

Laboratory data included increased serum cortisol concentrations with no diurnal variation along with a markedly elevated plasma ACTH level (Table). Urinary 17-hydroxycorticosteroid and 17-ketosteroid excretions were also increased (Table). Plasma renin activity and aldosterone concentration were suppressed. On the other hand, plasma levels of atrial natriuretic peptide were elevated. Hypokalemia of 2.7 mmol/L was found, along with metabolic alkalosis and excessive kaliuresis. The level of fasting blood sugar was 145 mg/dL. An abdominal computed tomographic scan showed diffuse enlargement of both adrenal glands. The diagnosis of ectopic ACTH syndrome produced by small-cell lung cancer was made.

View this table: [in this window] [in a new window]   Table 1. Hormonal Values

The patient received three times a combination chemotherapy (Fig 1) consisting of 120 mg/d cisplatin (1 day each: September 2, September 22, and October 12) and 150 mg/d etoposide (3 days each: September 2 through 4, September 22 through 24, and October 12 through 14). BP was controlled with long-acting nifedipine (80 mg/d) and bisoprolol (5 mg/d). Hypokalemia was treated with potassium chloride supplementation (30 to 150 mmol/d) and spironolactone (200 mg/d). Over the 2 months, the patient showed a gradual clinical improvement. The atelectasis and pleural effusion disappeared, but the size of the lung tumor remained unaltered. BP was well controlled, and plasma potassium concentration was within a normal range (Fig 1). Serum cortisol at 8 AM declined slightly but was still elevated on October 22 (Table). Furthermore, plasma ACTH levels at 8 AM remained high (Table).

View larger version (31K): [in this window] [in a new window]   Figure 1. Sequential changes in plasma OLC level, urinary OLC excretion, serum potassium concentration, and mean BP during 2 months after hospital admission. The patient received combination chemotherapy three times.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Fig 1 shows the changes in plasma and urinary OLC levels, serum potassium concentrations, and BP levels in response to treatment including chemotherapy. A marked increase in plasma OLC levels was found concomitantly with high BP and hypokalemia during the first 2 weeks. The maximum plasma OLC level was 3571 pmol/L on September 8 and was associated with premature ventricular contractions but not with ST depression and U wave. The maximum urinary OLC excretion was 1155 pmol/d on September 6. Plasma and urinary OLC levels gradually decreased in parallel with the decline in BP and rise in potassium concentration.

A positive correlation was observed between plasma OLC level and urinary OLC excretion (r=.48, P<.05). Plasma OLC level correlated with systolic BP (Fig 2A, r=.53, P<.01) and mean BP (r=.47, P<.05). A significant relation was also found between urinary OLC excretion and diastolic BP (r=.43, P<.05).

View larger version (12K): [in this window] [in a new window]   Figure 2. Relation among plasma OLC level, BP, and serum potassium concentration. There was a significant correlation between systolic BP (SBP) and plasma OLC level (A). Similarly, serum potassium concentration correlated significantly with plasma OLC level (B). Mean BP (MBP) increased significantly as serum potassium concentration decreased (C).

Plasma and urinary OLC levels correlated with serum potassium concentration (Fig 2B; plasma: r=-.62, P<.01; urine: r=-.64, P<.01) and with serum sodium-potassium ratio (plasma: r=.72, P<.01; urine: r=.64, P<.01). Serum potassium concentration correlated with BP values (systolic BP: r=-.62, P<.01; diastolic BP: r=-.66, P<.01; mean BP [Fig 2C]: r=-.67, P<.01). Serum sodium-potassium ratio was related to all BP values (data not shown). Thus, the best correlations were between plasma OLC and serum sodium-potassium ratio and between serum potassium and mean BP.

The major OLC peak in plasma appeared at 27 to 28 minutes and coincided with that of authentic ouabain on HPLC (Fig 3). Another second minor peak was found at 35 to 36 minutes. Two OLC peaks with similar elution times were found from urine on HPLC, but the second peak was more prominent. Fig 4 shows the effects on [³H]ouabain binding to human red blood cells of authentic ouabain and two OLCs from urine. The first OLC peak (0.5 pmol ouabain equivalents) inhibited [³H]ouabain binding by 30±2% (n=5), and the degree of inhibition was comparable to that produced by authentic ouabain (0.5 pmol, 34±4%, n=5). In contrast, the effect of the second OLC peak (0.5 pmol ouabain equivalents) was negligible.

View larger version (12K): [in this window] [in a new window]   Figure 3. Reversed-phase HPLC of C18 extracts of 5 mL pooled plasma. Bound materials were eluted with a linear acetonitrile gradient (0% to 30% in 30 minutes) after washing with water. One-minute fractions were collected and assayed for ouabain. Arrow indicates the elution point of authentic ouabain under the conditions used.

View larger version (20K): [in this window] [in a new window]   Figure 4. Inhibition of [3H]ouabain binding to human erythrocytes by authentic ouabain and OLCs derived from patient urine. Authentic ouabain inhibited [3H]ouabain binding in a dose-related manner. OLC (0.5 pmol; based on radioimmunoassay) in fraction 27-28 on reversed-phase HPLC inhibited [3H]ouabain binding to a degree comparable to that of authentic ouabain. However, the effect of the same amount of OLC in fraction 36-37 was negligible.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Tumorous secretion of ACTH is one of the many humoral syndromes of cancer, accounting for about 15% to 20% of cases of Cushing's syndrome from all causes.²⁴ Small-cell lung cancer is one of the major causes of ectopic ACTH syndrome. For the majority of patients with ectopic ACTH secretion, plasma ACTH concentrations are often very high. The clinical picture is typified by the sudden appearance and rapid progression of signs of extreme hypercortisolemia, including hypertension, edema, weakness, hypokalemia, and glucose intolerance.²⁴ These signs may be accompanied by manifestations of the malignancy causing the hypercortisolism, as were found in our patient.

In ectopic ACTH syndrome, hypertension has been attributed to cortisol inactivation overload, giving rise to mineralocorticoid-type hypertension through cortisol occupancy of mineralocorticoid receptors.²⁵ Although sodium retention and volume expansion are believed to cause the hypertension in the states of mineralocorticoid excess, the mechanisms involved are not certain. One concept is that sodium retention stimulates release of a sodium pump inhibitor with a digitalis-like action.^{6 7 8 9 10} One of its effects is to counteract the expansion by natriuresis; another is to increase the sodium content of vascular smooth muscle, thereby causing vasoconstriction and hypertension. Consistent with this view, elevated plasma OLC has been found in patients with primary aldosteronism.^{26 27 28} According to a recent report,²⁸ elevated plasma OLC has been observed also in 60% of patients with essential hypertension in whom the relation of BP with body electrolytes is thought to be similar to that in primary aldosteronism.^{4 5}

In our hypertensive patient with ectopic ACTH syndrome, initial plasma OLC levels were markedly elevated and were 40-fold the normal range of the subject. OLC concentrations decreased, with partial correction of the hypercortisolism, after chemotherapy. In accordance with the fall in OLC levels, BP was well controlled, and positive correlations were observed among plasma OLC level, urinary OLC excretion, and BP values. It has been demonstrated that OLC from human circulation is vasoactive.²⁹ Several groups of investigators have demonstrated that long-term administration of ouabain gradually leads to the development of hypertension in rats.^{18 19 21} Recent studies with rats immunized against ouabain provided evidence for the participation of OLC in reduced renal mass–saline hypertension and sodium-induced hypertension in Dahl salt-sensitive rats.^{17 20} Therefore, OLC may exert a hypertensinogenic action. These findings suggest that increased circulating OLC could contribute in part to hypertension in this patient, as proposed by many investigators.

Furthermore, to our knowledge this is the first demonstration that plasma OLC level has a significant relation with urinary OLC excretion. This finding suggests that the major OLCs in plasma and urine may be the same substances, at least in our patient. Although the presence of endogenous OLC is still in some doubt,³⁰ we confirmed in plasma and urine the presence of a ouabain-immunoreactive peak coincident with the elution time of authentic ouabain on a reversed-phase HPLC system. Moreover, this ouabain-immunoreactive peak at least from urine showed a digitalis-like binding activity. However, we have some reservations about the exact identity of OLC and authentic ouabain based on our own experience²³ and a recent suggestion.¹³

What could be the mechanism or mechanisms that led to the hypersecretion of OLC in this patient? A recent report indicated that ACTH stimulates OLC secretion from adrenal glands.³¹ Furthermore, in some individuals, primary adrenal overproduction of OLC may account for the elevated plasma levels and high BP.³² However, it is unlikely that the OLC secretion was solely under ACTH regulation in this patient because ACTH overproduction and a high cortisol level were still observed despite the fall in OLC (Fig 1 and Table). As mentioned above, hypertension is attributed to cortisol, giving rise to mineralocorticoid-type hypertension in ectopic ACTH syndrome.²⁵ Therefore, it is more likely that sodium retention and volume expansion suggested by increased atrial natriuretic peptide concentration and a suppressed renin-aldosterone system (Table) caused a marked rise of OLC level in our patient. Although the effects of spironolactone and its metabolite canrenone on the pressor action and/or synthesis of OLC cannot be excluded,³³ the fall in OLC may be mainly ascribed to the inhibition with spironolactone of the cortisol binding to the mineralocorticoid receptor and, hence, the mineralocorticoid excess.

The significance of the relation of OLC levels with potassium concentration or sodium-potassium ratio in our patient is uncertain. A rational sequence of events in our case is that mineralocorticoid excess resulted in renal excretion of potassium and renal retention of sodium, the latter increasing OLC. Therefore, it may simply reflect the correction with spironolactone of the state of mineralocorticoid excess. However, a fundamental role of the sodium pump is to maintain the normal distribution of sodium and potassium to the different fluid compartments. The cardiac glycosides inhibit the sodium pump and increase the serum potassium concentration due to the release of potassium from the cells. The digoxin-specific Fab antibody fragments decrease serum potassium concentration by blocking the action of cardiac glycosides.³⁴ Endogenous OLC likely increases the serum potassium concentration in a manner similar to exogenous cardiac glycosides. Several studies point to a close connection between OLC or sodium pump inhibitors and serum potassium concentration.^{35 36} Bagrov et al³⁶ have recently observed a significant correlation between serum potassium concentration and digoxin-like factor in patients with acute myocardial infarction. Furthermore, we found a consistent fall in serum potassium concentration in the absence of OLC action in animals immunized against ouabain (unpublished observations, 1994). Taken together, these findings indicate an important role of OLC in potassium homeostasis through the regulation of sodium pump (Na⁺,K⁺-ATPase) activity. Since OLC inhibits the sodium pump and increases serum potassium, it is more likely that the decrease in serum potassium may precede and trigger the elevation of OLC levels. However, because there is no evidence for this idea in the present study or elsewhere, further evaluation is clearly necessary in future studies.

Serum potassium concentration negatively correlated with all BP parameters in our patient. A similar inverse correlation between BP and plasma potassium concentration has also been reported in patients with primary aldosteronism and essential hypertension.^{4 5 37} Furthermore, it has been known that potassium depletion increases BP in normotensive and essential hypertensive subjects.^{38 39} The pathogenesis of potassium-induced changes in BP has been attributed in part to suppression of the electrogenic sodium pump in vascular smooth muscle.⁴⁰ Furthermore, sodium balance has been closely related to potassium-induced changes in BP, but OLC has not been measured during potassium depletion in a previous study.³⁹ If the increase in OLC is caused by the changes in potassium balance, OLC also may play a mediating role for potassium depletion in causing an increase in BP. It appears that at least in our patient, the decreased potassium and increased OLC both suppressed the sodium pump, resulting in vasoconstriction via electrogenic depolarization of the vascular smooth muscle cell.

A limitation of our study is that our interpretations are based on correlations, and the data cannot prove a causal relation between OLC and hypertension. However, it is impossible to directly prove the hypertensive action of OLC in humans without the development of antagonists blocking OLC action. The other limitation is that we treated the patient with several antihypertensive agents. We measured BP during the early morning to limit the influence of these drugs on BP, but we cannot completely exclude the effects of antihypertensive agents on BP and OLC.

In conclusion, a serial OLC measurement in the circulation suggested the contribution of OLC to mineralocorticoid-type hypertension in our patient with ectopic ACTH syndrome. The reproducibility of our findings remains to be determined.

	Selected Abbreviations and Acronyms

 

ACTH = corticotropin BP = blood pressure HPLC = high-performance liquid chromatography OLC = ouabainlike compound

	Acknowledgments

 
This study was supported in part by a Grant-in-Aid (07457164) from the Ministry of Education, Science, and Culture, Japan, and a grant from the Japan Cardiovascular Research Foundation. We are indebted to Drs Etsu Ohno, Hideo Yoshida, and Yutaka Syuzui for clinical care of this patient and Yukari Kawabata for technical assistance.

	Footnotes

 
Reprint requests to Atsuo Goto, MD, Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.

Received March 14, 1996; first decision April 4, 1996; accepted April 25, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Lifton RP. Liddle's syndrome: heritable human hypertension caused by mutations in the ß subunit of the epithelial sodium channel. Cell. 1994;79:407-414.[Medline] [Order article via Infotrieve]
2. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel J-M. A chimaeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-suppressible aldosteronism and human hypertension. Nature. 1992;355:262-265.[Medline] [Order article via Infotrieve]
3. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11ß-hydroxysteroid dehydrogenase. Nat Genet. 1995;10:394-399.[Medline] [Order article via Infotrieve]
4. Beretta-Piccoli C, Davies DL, Boddy K, Brown JJ, Cumming AMM, East BW, Fraser R, Lever AF, Padfield PL, Semple PF, Robertson JIS, Weidman P, Williams ED. Relation of arterial pressure with body sodium, body potassium and plasma potassium in essential hypertension. Clin Sci. 1982;63:257-270.[Medline] [Order article via Infotrieve]
5. Beretta-Piccoli C, Davies DL, Brown JJ, Ferris JB, Fraser R, Lever AF, Morton JJ, Robertson JIS. The relation of arterial pressure with plasma and body electrolytes is similar in Conn's syndrome and essential hypertension. Clin Sci. 1982;63:89s-92s.
6. Haddy FJ, Overbeck HW. The role of humoral agents in volume expanded hypertension. Life Sci. 1976;19:935-948.[Medline] [Order article via Infotrieve]
7. De Wardener HE, MacGregor GA. Dahl's hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: its possible role in essential hypertension. Kidney Int. 1980;18:1-9.[Medline] [Order article via Infotrieve]
8. Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca²⁺ stores and cell responsiveness. Am J Physiol. 1993;264:C1367-C1387.[Abstract/Free Full Text]
9. Goto A, Yamada K, Yagi N, Yoshioka M, Sugimoto T. Physiology and pharmacology of endogenous digitalis-like factors. Pharmacol Rev. 1992;44:377-399.[Medline] [Order article via Infotrieve]
10. Hollenberg NK, Graves SW. Koch's postulates and the digitalis-like factor. Hypertens Res. 1995;18:1-6.[Medline] [Order article via Infotrieve]
11. Hamlyn JM, Blaustein MP, Bova S, Ducharme DW, Harris DW, Mandel F, Mathews WR, Ludens JH. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A. 1991;88:6259-6263.[Abstract/Free Full Text]
12. Tymiak AA, Norman JA, Bolger M, DiDonato GC, Lee H, Parker WL, Lo L-C, Berova N, Nakanishi K, Haber E, Haupert GT. Physicochemical characterization of an ouabain isomer isolated from bovine hypothalamus. Proc Natl Acad Sci U S A. 1993;90:8189-8193.[Abstract/Free Full Text]
13. Zhao N, Lo L-C, Berova N, Nakanishi K, Tymiac AA, Ludens JH, Haupert GT. Na,K-ATPase inhibitors from bovine hypothalamus and human plasma are different from ouabain: nanogram scale CD structural analysis. Biochemistry. 1995;34:9893-9896.[Medline] [Order article via Infotrieve]
14. Lichtstein D, Gati I, Samuelov S, Berson D, Rozenman Y, Landau L, Deutsch J. Identification of digitalis-like compounds in human cataractous lenses. Eur J Biochem. 1993;216:261-268.[Medline] [Order article via Infotrieve]
15. Tamura M, Harris TW, Konishi F, Inagami T. Isolation and characterization of an endogenous Na⁺,K⁺-ATPase-specific inhibitor from pig urine. Eur J Biochem. 1993;211:317-327.[Medline] [Order article via Infotrieve]
16. Graves SW, Glatter KA, Lazarus JM, Williams GH, Hollenberg NK. Volume expansion in renal failure patients: a paradigm for a clinically relevant [Na,K]ATPase inhibitor. J Cardiovasc Pharmacol. 1993;22(suppl 2):S54-S57.
17. Yamada K, Goto A, Hui C, Yagi N, Nagoshi H, Sasabe M, Sugimoto T. Role of ouabainlike compound in rats with reduced renal mass-saline hypertension. Am J Physiol. 1994;266:H1357-H1362.[Abstract/Free Full Text]
18. Yuan C, Manunta P, Hamlyn JM, Chen S, Bohen E, Yeun J, Haddy FJ, Pamnani M. Long-term ouabain administration produces hypertension in rats. Hypertension. 1993;22:178-187.[Abstract/Free Full Text]
19. Manunta P, Rogowski AC, Hamilton BP, Hamlyn JM. Ouabain-induced hypertension in the rat: relationships among plasma and tissue ouabain and blood pressure. J Hypertens. 1994;12:569-576.[Medline] [Order article via Infotrieve]
20. Gomez-Sanchez EP, Gomez-Sanchez CE, Fort C. Immunization of Dahl SS/jr with an ouabain conjugate mitigates hypertension. Am J Hypertens. 1994;7:591-596.[Medline] [Order article via Infotrieve]
21. Huang BS, Huang X, Harmsen E, Leenen FHH. Chronic central versus peripheral ouabain, blood pressure, and sympathetic activity in rats. Hypertension. 1994;23:1087-1090.[Abstract/Free Full Text]
22. Goto A, Yamada K, Yagi N, Nagoshi H, Hui C, Sugimoto T. Novel concepts on the roles of ouabainlike compound in hypertension. J Hypertens. 1992;10:S50. Abstract.
23. Goto A, Yamada K, Ishii M, Sugimoto T. Release of endogenous digitalis-like factor with sodium loading. N Engl J Med. 1989;320:124-125.[Medline] [Order article via Infotrieve]
24. Odell WD. Ectopic ACTH secretion, a misnomer. Endocrinol Metab Clin N Am. 1991;20:371-379.[Medline] [Order article via Infotrieve]
25. Ulick S, Jennifer ZW, Blumenfeld JD, Pickering TG. Cortisol inactivation overload: a mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotrophin syndrome. J Clin Endocrinol Metab. 1992;74:963-967.[Abstract]
26. Masugi F, Ogihara T, Hasegawa T, Tomii A, Nagano M, Higashimori K, Kumahara K, Terano Y. Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism. Biochem Biophys Res Commun. 1986;135:41-45.[Medline] [Order article via Infotrieve]
27. Naruse K, Naruse M, Tanabe A, Yoshimoto T, Tanaka M, Watanabe Y, Kurimoto F, Horiba N, Tamura M, Inagami T, Demura H. Does plasma immunoreactive ouabain originate from the adrenal gland? Hypertension. 1994;23(suppl I):I-102-I-105.
28. Rossi G, Manunta P, Hamlyn JM, Pavan E, De Toni R, Semplicini A, Pessina AC. Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationships with plasma renin, aldosterone and blood pressure levels. J Hypertens. 1995;13:1181-1192.[Medline] [Order article via Infotrieve]
29. Bova S, Blaustein MP, Ludens JH, Harris DW, Ducharme DW, Hamlyn JM. Effects of an endogenous ouabainlike compound on heart and aorta. Hypertension. 1991;17:944-950.[Abstract/Free Full Text]
30. Doris PA, Jenkins LA, Stocco DM. Is ouabain an authentic endogenous mammalian substance derived from the adrenal? Hypertension. 1994;23:632-638.[Abstract/Free Full Text]
31. Laredo J, Hamilton BP, Hamlyn JM. Ouabain is secreted by bovine adrenocortical cells. Endocrinology. 1994;135:794-797.[Abstract]
32. Manunta P, Evans G, Hamilton BP, Gann D, Resau J, Hamlyn JM. A new syndrome with elevated plasma ouabain and hypertension secondary to an adrenocortical tumor. J Hypertens. 1992;10(suppl 6):27. Abstract.
33. Pamnani MB, Whitehorn WV, Clough DL, Haddy FJ. Effects of canrenone on blood pressure in rats with reduced renal mass. Am J Hypertens. 1990;3:188-195.[Medline] [Order article via Infotrieve]
34. Woolf AD, Wenger T, Smith TW, Levojoy FH. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med. 1992;326:1739-1744.[Abstract]
35. Szylman P, Wolach B, Winaver J, Panett R, Cohen P, Schenkman L, Better OS. Nonazotemic hyperkalemia with renal and extrarenal defects in potassium transport: association with high levels of digoxin-like immunoreactive factor. J Lab Clin Med. 1990;116:315-326.[Medline] [Order article via Infotrieve]
36. Bagrov AY, Kuznetsova EA, Fedorova OV. Endogenous digoxin-like factor in acute myocardial infarction. J Intern Med. 1994;235:63-67.[Medline] [Order article via Infotrieve]
37. Bulpit CJ, Shipley MJ, Semmence A. Blood pressure and plasma sodium and potassium. Clin Sci. 1981;61:85S-87S.
38. Krishna GG, Miller E, Kapoor S. Increased blood pressure during potassium depletion in normotensive men. N Engl J Med. 1989;320:1177-1182.[Abstract]
39. Krishna GG, Kapoor S. Potassium depletion exacerbates essential hypertension. Ann Intern Med. 1991;115:77-83.
40. Haddy FJ. Potassium effects on contraction in arterial smooth muscle mediated by Na⁺,K⁺-ATPase. Fed Proc. 1983;42:239-245.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				K. Ihenetu, H. M. Qazzaz, F. Crespo, R. Fernandez-Botran, and R. Valdes Jr Digoxin-Like Immunoreactive Factors Induce Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Clin. Chem., July 1, 2007; 53(7): 1315 - 1322. [Abstract] [Full Text] [PDF]

				M. P. Blaustein, J. Zhang, L. Chen, and B. P. Hamilton How does salt retention raise blood pressure? Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R514 - R523. [Abstract] [Full Text] [PDF]

				I. Dostanic-Larson, J. N. Lorenz, J. W. Van Huysse, J. C. Neumann, A. E. Moseley, and J. B Lingrel Physiological role of the {alpha}1- and {alpha}2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R524 - R528. [Abstract] [Full Text] [PDF]

				J. H. Kaplan The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase PNAS, November 1, 2005; 102(44): 15723 - 15724. [Full Text] [PDF]

				I. Dostanic-Larson, J. W. Van Huysse, J. N. Lorenz, and J. B Lingrel From The Cover: The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation PNAS, November 1, 2005; 102(44): 15845 - 15850. [Abstract] [Full Text] [PDF]

				J. R. Shah, J. Laredo, B. P. Hamilton, and J. M. Hamlyn Different Signaling Pathways Mediate Stimulated Secretions Of Endogenous Ouabain and Aldosterone From Bovine Adrenocortical Cells Hypertension, January 1, 1998; 31(1): 463 - 468. [Abstract] [Full Text] [PDF]

				M. Ferrandi, P. Manunta, S. Balzan, J. M. Hamlyn, G. Bianchi, and P. Ferrari Ouabain-like Factor Quantification in Mammalian Tissues and Plasma : Comparison of Two Independent Assays Hypertension, October 1, 1997; 30(4): 886 - 896. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goto, A. Articles by Omata, M. Search for Related Content PubMed PubMed Citation Articles by Goto, A. Articles by Omata, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB OUABAIN