Enhanced Na+/H+ exchange in Cushing's syndrome reflects functional hypermineralocorticoidism.

BACKGROUND: Patients with Cushing's syndrome exhibit a bimodal distribution of maximal rates of the erythrocyte amiloride-sensitive Na+/H+ exchange (NHE). Enhanced erythrocyte NHE has recently been found in patients with primary aldosteronism. OBJECTIVE: To test the hypothesis that occult hypermineralocorticoidism in a subset of patients with Cushing's syndrome is responsible for the greater than normal NHE. METHODS: NHE was measured as maximal initial rate (Vmax) of amiloride-inhibited efflux of H+ into an alkaline Na+-containing medium, for 47 patients with hypercortisolism (20 with pituitary adenomas, 18 with adrenal adenomas, and nine with ectopic production of adrenocorticotropin). Clinical appearance, blood pressure levels, plasma aldosterone and deoxycorticosterone levels, serum electrolytes, and urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios were assessed for all patients. Twenty patients (10 with greater than normal NHE and 10 with low-to-normal NHE) were randomly selected from 47 patients with hypercortisolism, and treated with 200 mg/day spironolactone for 7 days. NHE in these patients was assessed before starting the treatment and 2 days after its cessation. RESULTS: Greater than normal NHE (Vmax) was associated with peripheral edema, high diastolic blood pressure, hypokalemia, and high urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios. The enhanced NHE was rapidly normalized by treatment with spironolactone. CONCLUSION: Erythrocyte NHE in patients with hypercortisolism and functional hypermineralocorticoidism is greater than normal due to incomplete peripheral conversion of cortisol (which binds to mineralocorticoid receptors) into metabolically inactive cortisone.

Rhabdomyolysis associated with clozapine treatment in a patient with decreased calcium-dependent potassium permeability of cell membranes.

A 21-year-old patient developed rhabdomyolysis during his nineteenth week of treatment with clozapine for drug-resistant schizophrenia. No risk factors for rhabdomyolysis were found, but the calcium-dependent potassium efflux, normally responsible for membrane hyperpolarization and muscle refractoriness, was severely decreased in the patient's red blood cells. Clozapine is speculated to cause rhabdomyolysis in patients with defective calcium-activated K+ channels.

Xiphodynia masking acute myocardial infarction: a diagnostic cul-de-sac.

A 52-year-old hypertensive woman is described in whom a clinically evident diagnosis of xiphodynia, the painful xiphoid process, complicated the diagnosis of impending myocardial infarction. The authors suggest that xiphodynia be considered a second-line assumption after more dangerous conditions have been thoroughly ruled out.

Enhanced erythrocyte Na+/H+ exchange predicts diabetic nephropathy in patients with IDDM.

Diabetic nephropathy develops in a subset of patients with an apparently hereditary predisposition. Microalbuminuria and elevated arterial pressure have been proposed as predictors of nephropathy but both appear when renal damage is impending. Enhanced sodium-hydrogen exchange in the cell membranes of diabetic patients is an early marker of diabetic nephropathy but its predictive value has not been assessed. In this study, sodium-hydrogen exchange was measured in erythrocytes as an initial velocity of amiloride-inhibited H+ efflux (pH 6.35-6.45) into a Na+ - containing medium (pH 7.95-8.05) in 156 non-microalbuminuric insulin-treated diabetic patients (98 women, 58 men, age 33+/-8 years, diabetes duration prior to enrollment 15+/-4 years) during 8 years of follow-up. Enhanced erythrocyte sodium-hydrogen exchange predicted diabetic nephropathy alone and in association with a familial tendency to hypertension/nephropathy with 86 and 96% sensitivity, and 80% specificity. Thus, sodium-hydrogen exchange appears to detect a subset of diabetic patients prone to develop renal damage, in whom a more intensive treatment modality might be considered.

Membrane ion transport in Bartter's syndrome: evidence for a new syndrome subtype.

Fifteen patients with Bartter's syndrome (hyponatremic hypochloremic hypokalemic metabolic alkalosis) were compared with 15 healthy volunteers. Red blood cell Na+/H+ and Cl-/HCO3- exchanges were enhanced in all patients with Bartter's syndrome. In calciuric normomagnesemic patients, sensitive to nonsteroidal anti-inflammatory drugs (classic Bartter's syndrome), red blood cell Na+,K+,2Cl- cotransport was markedly reduced, calcium-dependent K+ permeability was moderately increased, and up to 60% of sodium permeability was represented by cAMP-activated fraction (presumably human analog of beta-isoform of Na+/H+ exchange). In noncalciuric hypomagnesemic patients insensitive to indomethacin (Gitelman's syndrome), Na+,K+,2Cl- cotransport was enhanced, Na+ permeability was increased due to calmodulin-dependent fraction, and calcium-dependent K+ permeability was markedly enhanced. A new subtype of Bartter-like syndrome ("variant Bartter's syndrome") has been described in which calciuria, hypomagnesemia, and insensitivity to nonsteroidal anti-inflammatory drugs were associated with decreased Na+,K+,2Cl- cotransport, enhanced calmodulin-activated fraction of Na+ influx, and reduced calcium-dependent K+ permeability.

Enhanced red cell sodium-hydrogen exchange in microvascular angina.

OBJECTIVES: Enhanced calcium content in arterial smooth muscle cells and altered reactivity of coronary vessels to alkalinization have been reported in angina pectoris due to impaired motility of coronary arteries. An altered function of sodium-hydrogen exchange, a ubiquitous membrane transport system that links proton efflux to calcium drifts, may mediate these phenomena. DESIGN AND SUBJECTS: Twenty patients with microvascular angina (stable effort angina, reversible perfusion defects during effort thallium 201 heart scintigraphy, and angiographically normal coronary arteries) were compared to 20 patients with stable effort angina due to coronary atherosclerosis and 20 healthy subjects. The sodium-hydrogen exchange was defined as the initial fraction of the amiloride-sensitive proton efflux from red cells with inhibited anion exchanger (pHi 6.00-6.05) into an Na(+)-containing medium (pHo 8.00-8.05). 12-0-tetradecanoylphorbol-13-acetate (TPA, 600 nmol.l-1) and staurosporine (100 nmol.l-1) were used as phosphorylation modulators in vitro. RESULTS: The mean red blood cell Na+/H+ exchange was increased in patients with microvascular angina (451 +/- 37 vs 142 +/- 17 and 124 +/- 21 umol H+.1 cells-1.min-1, P < 0.01). TPA and staurosporine abolished differences between the groups. CONCLUSIONS: Microvascular angina is associated with enhanced Na+/H+ exchange in erythrocytes, probably due to more extensive phosphorylation of the membrane antiporter sites.

Amiloride-sensitive Na+/H+ exchange in erythrocytes of patients with NIDDM: a prospective study.

Intensive treatment of non-insulin-dependent diabetes mellitus (NIDDM) decreases the rate of microvascular complications, but is associated with increased incidence of cardiovascular morbidity. Enhanced permeability of plasma membranes for sodium (e.g. sodium-hydrogen exchange, NHE) may predict the subset of diabetic patients for whom intensive modalities of treatment are indicated despite their potential risk. However, the accuracy of NHE as a marker of microangiopathy has not been assessed. In this study NHE as initial velocity of amiloride-inhibited H+ efflux from erythrocytes (pHi 6.35-6.45) into an Na(+)-containing medium (pHo 7.95-8.05), was estimated during 8 years of follow-up in 138 non-microalbuminuric diabetic patients (74 women, 64 men, age 52 +/- 4 years) treated with antihyperglycaemic drugs for 14 +/- 2 years. Appearance of microalbuminuria, overt proteinuria, azotaemia and retinopathy was assessed annually. Enhanced erythrocyte NHE predicted diabetic nephropathy alone and in association with a family history of hypertension and/or nephropathy with a sensitivity of 86 and 93%, respectively. No association was found between NHE and retinopathy in NIDDM. It is concluded that assessment of erythrocyte NHE can identify a subset of patients likely to develop renal damage, for whom an aggressive treatment approach might be considered.

Spironolactone prevents Na+/H+ exchange enhancement in primary aldosteronism.

The study was undertaken to determine the possible effect of an aldosterone antagonist, spironolactone (SP), on red blood cell sodium-hydrogen exchange (NHE) enhancement in primary aldosteronism (PA) and essential hypertension (EH). NHE was measured as the amiloride-inhibited fraction of H+ efflux (V max) from erythrocytes (pHi 6.40 +/- 0.05) into a Na+-containing medium (pHo 8.00 +/- 0.05). Subjects were 12 hypertensive patients with aldosterone-producing adrenal adenoma (six treated with 200 mg/day spironolactone for an least 5 days and six drug-free), 20 essential hypertensives (10 treated with the same regimen of spironolactone and 10 drug-free), and 20 healthy controls. Treatment with spironolactone decreased NHE in PA patients but did not change the mean NHE in essential hypertensives. It is concluded that SP may be useful to differentiate between elevated NHE in PA and essential hypertension.

Increased Na(+)-H+ exchange in red blood cells of patients with primary aldosteronism.

We measured Na(+)-H+ exchange as the amiloride-inhibited fraction of H+ efflux from red blood cells into a sodium-containing medium (pHo 7.95 to 8.05) at pHi values of 6.05 to 6.15, 6.35 to 6.45, 6.95 to 7.05, and 7.35 to 7.45 in 12 drug-free patients with primary aldosteronism before and after excision of histologically proven aldosterone-producing adrenal adenoma, 12 drug-free essential hypertensive patients, and 12 healthy control subjects. Red blood cell Na(+)-H+ exchange was increased in patients with primary aldosteronism similarly to the mean exchanger velocity in essential hypertensive patients compared with values in healthy subjects (334 +/- 25 and 310 +/- 29 versus 139 +/- 21 mumol H+/L cells per minute, respectively; P < .001 and .01). The kinetic parameters of Na(+)-H+ exchange returned to normal on day 2 after removal of the aldosterone-producing mass. Km for [Na+]o was not affected by aldosterone, whereas Km for [H+]i was decreased in patients with primary aldosteronism. The kinetic characteristics did not differ in essential hypertensive patients and control subjects. Protein kinase C inhibition in vitro by calphostin C (60 nmol/L) increased Km for [H+]i and caused up to a 65% suppression of Na(+)-H+ exchange (pHi 6.05 to 6.15). while diminishing Km for [Na+]o in red blood cells of patients with primary aldosteronism. The calmodulin antagonist W-13 (60 mmol/L) decreased exchanger velocity and increased Km for both H+ and Na+. We conclude that aldosterone stimulates red blood cell Na(+)-H+ exchange by a nongenomic mechanism that augments the exchanger affinity to Na+ and H+. In primary aldosteronism, protein kinase C and calmodulin seem to have synergistic stimulatory effects on red blood cell Na(+)-H+ exchange, and both increase the affinity of the exchanger to H+, while their effect on Na+ binding is opposite.

Lactic acidosis and fatal myocardial failure due to clozapine.

OBJECTIVE: To describe a patient with neutropenic fever complicated by hyperglycemia, lactic acidosis, and fatal myocardial failure associated with clozapine therapy. CASE SUMMARY: A 37-year-old Ashkenazic Jewish man was admitted for agranulocytosis and fever, which developed after 11 weeks of clozapine monotherapy for drug-resistant schizophrenia. Complete blood counts and a routine serum chemical analysis had been normal before the treatment was initiated, and remained within normal limits during the first 10 weeks of the treatment. On the day of admission, the patient deteriorated rapidly and developed extreme hyperglycemia, severe lactic acidosis, recurrent cardiac arrest, cardiogenic shock, and coma. He died 36 hours later despite intensive treatment. DISCUSSIONS: Clozapine intake reduced fatal aganulocytosis, associated with hyperglycemia, lactic acidosis, and heart failure. White blood cell count monitoring was insufficient to predict these adverse effects. CONCLUSIONS: Clozapine should be avoided in high-risk patients (e.g., the elderly, women, Ashkenazic Jews).

Common variable immunodeficiency associated with myelocathexis and altered membrane sodium-proton antiport.

Alterations in protein kinase C (PKC) activity have been implied in the pathogenesis of common variable immunodeficiency (CVID). We analyzed amiloride-sensitive red blood cell Na+/H+ exchange (sodium-proton antiport, SPA) and its response to protein kinase stimulation in a patient with CVID. Compared with healthy subjects or patients with sepsis, a unique pattern of SPA activation has been shown. The patient's SPA was decreased and unresponsive to PKC stimulation, whereas stimulation by insulin, a tyrosine kinase activator, restored SPA activity. An alteration of serine-threonine phosphorylation is suggested as a possible mechanism for the immune failure.

[Progress of lymphoproliferative disease associated with disseminated Kaposi's sarcoma].

A 73-year-old woman with a lymphoproliferative disorder had successive stages of reactive lymphadenopathy in sequence, a multifocal type of Castleman's disease and angioimmunoblastic lymphadenopathy. The disease ran an aggressive course and was associated with disseminated Kaposi's sarcoma. The linkage between the various types of lymphoproliferative disorders that presented in the same patient, as well as the association with Kaposi's sarcoma, are discussed.

Red cell Na+/H+ exchange and B cell alloantigen 883 (D8/17) in patients with acute rheumatic fever and inactive rheumatic heart disease.

The association of Na+/H+ antiport with 883 alloantigen was studied in patients with rheumatic disease. Simultaneous measurements were made of red cell Na+/H+ exchange and 883 alloantigen in microlymphocytotoxic test with D8/17 monoclonal antibodies in 20 patients with acute rheumatic fever, 20 patients with inactive rheumatic heart disease, 20 patients with atherosclerotic heart disease (stable anginal syndrome), and 20 healthy subjects. The number of 883(+) B cells and the Na+/H+ antiport activity were increased in rheumatic fever compared to healthy controls: 24.8 +/- 0.4 vs. 11.1 +/- 1.0% cells, 431 +/- 43 vs 121 +/- 12 micromol H+/l cells in min, respectively; p < 0.001; and in patients with rheumatic heart disease compared to patients with atherosclerotic heart disease; 25.7 +/- 1.8 vs. 9.8 +/- 1.1% cells, 482 +/- 73 vs. 124 +/- 12 micromol H+/l cells in min, respectively; p < 0.001.