p53 mutations in hairy cell leukemia.

We have studied the frequency of p53 mutations in genomic DNA extracted from peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR-SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17 cases, corresponding to a frequency of 28%. In four cases, mutations were localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to be mutated in seven cases. The mutations found could be divided into three major categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations. None of the three transitions found occurred at CpG dinucleotides. The rate of p53 mutations found in this large cohort of HCL patients is unexpectedly high as in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome. The character of the mutations we have found is entirely different from that described in other hematologic malignancies.

Hypertension associated with early stage kidney disease. Complementary roles of circulating renin, the body sodium/volume state and duration of hypertension.

Interrelations among blood pressure, exchangeable sodium, blood volume and plasma renin activity were studied in 40 normal subjects and in 40 patients with early stage kidney disease (mean plasma creatinine, 2 mg/100 ml). Findings in eight normotensive patients did not differ significantly from those in normal subjects. However, 32 hypertensive patients showed increases (p less than 0.05) in mean exchangeable sodium and in the products of the logarithm of plasma renin activity and exchangeable sodium or blood volume. In normal subjects, blood pressure did not correlate with any of the parameters measured. In the patients, it correlated significantly (p less than 0.05) with duration of hypertension (r = 0.70), exchangeable sodium (r = 0.34) and with sodium-renin (r = 0.38) or volume-renin (r = 0.30) products, but not with blood volume or circulating renin individually. Multiple regression analysis with blood pressure as a dependent variable, and duration of hypertension and the sodium-renin or volume-renin products as independent variables, revealed correlation coefficients of 0.77 and 0.76, respectively. These findings suggest that hypertension accompanying early stage kidney disease may depend at least partly on subtle abnormalities in the sodium volume-renin feedback mechanism as well as on a factor related to the duration of preexisting hypertension.

Relationship between blood pressure variability and serum dehydroepiandrosterone sulfate levels.

Decreased diurnal blood pressure variability and low dehydroepiandrosterone sulfate (DHEAS) levels are important predictors of cardiovascular morbidity and mortality. The aim of the study was to determine the relationship between DHEAS levels and diurnal blood pressure variability in normotensive subjects and in patients with essential hypertension of both genders. An ambulatory blood pressure monitor (ABPM), Meditech O2 device and radioimmunoassay were used for ambulatory blood pressure monitoring and the determination of DHEAS levels, respectively. A close correlation (P < .001) was found between the diurnal indices and plasma DHEAS levels of the 387 subjects (86 normotensive and 301 hypertensive patients) participating in the study. Decreased plasma DHEAS levels were associated in both genders, and in both normotensive and hypertensive patients with significantly (P < .001) lower diurnal indices. There was a close correlation (P < .001) between the age-related decrease in plasma DHEAS levels and diurnal indices in both genders. Systolic and diastolic blood pressure variability changed parallel to plasma DHEAS levels in both genders, whether hypertension was present or not. Additional investigations are needed to find out whether reduced DHEAS levels play a role in decreased diurnal indices or whether both can be traced back to one and the same cause.

Interactions between ouabain, atrial natriuretic peptide, angiotensin-II and potassium: effects on rat zona glomerulosa aldosterone production.

The effects of ouabain, atrial natriuretic peptide, angiotensin-II and potassium on aldosterone production by collagenase dispersed rat zona glomerulosa cells were studied. A-II and 10(-4) M ouabain-induced increases in aldosterone production was inhibited by 10(-9) M ANP at all potassium concentrations examined. 10(-4) M ouabain inhibited the A-II induced increase in aldosterone production at all potassium concentrations. The degree of this inhibition was smaller at higher potassium levels. Ouabain enhanced the inhibitory effect of ANP on A-II-induced aldosterone synthesis at all potassium concentrations. Interactions between A-II, ANP, ouabain and potassium may be of physiological significance in the regulation of aldosterone secretion.

Atrial natriuretic peptide (ANP) in patients with chronic renal failure on maintenance haemodialysis.

Atrial natriuretic peptide (ANP), a recently discovered cardiac hormone, is an important regulator of body fluid homeostasis. Twenty patients with established chronic renal failure and on maintenance haemodialysis were studied before and after dialysis with capillary dialysers. ANP was determined by RIA after extraction. Mean (+/- SD) pre-dialysis ANP concentration was 146 +/- 51 pg/ml and decreased significantly during dialysis to 68 +/- 38 pg/ml (p less than 0.001). Per cent and absolute changes in plasma ANP level correlated significantly with concomitant changes in body weight (r = 0.764; p less than 0.001 and r = 0.558; p less than 0.01, resp.) but not with changes in serum creatinine, blood pressure or serum electrolytes. The obtained results indicate that ANP levels in patients with chronic renal failure are elevated mainly due to fluid overload, and the rapid fall in ANP concentration observed during haemodialysis is caused by the removal of excess fluid from the body.

[Current questions concerning the pathomechanism of diabetic nephropathy]. / A diabeteses nephropathia patomechanizmusának aktuális kérdései.

Diabetic nephropathy has become, one of the most frequent causes of chronic renal failure in the industrialized countries. Basic and clinical research aimed at the clarification of the pathogenesis of diabetic kidney disease is of utmost importance. The role of non-enzymatic glycosylation, the polyol cycle, oxidative stress, various hormones and cytokines in the development of diabetic nephropathy is very likely. However, there is still no unifying concept about the relative importance and interaction of these factors. This paper reviews the most important directions and results of basic research centering on diabetic kidney disease. The coming years will likely bring the elaboration of a detailed theory of the pathogenesis and an even tighter coordination of basic and clinical research.

[Current issues in the diagnosis and therapy of diabetic nephropathy]. / A diabeteses nephropathia diagnosztikájának és terápiajának aktuális kérdései.

Diabetic nephropathy is one of the most frequent causes of chronic renal failure worldwide. Altogether, 35% of patients with insulin-dependent diabetes mellitus and a somewhat smaller percentage of patients with non-insulin-dependent diabetes mellitus ultimately develop diabetic kidney disease. Early diagnosis is of utmost importance since the development of diabetic nephropathy affects the general health, the carbohydrate metabolism of the patient, moreover it aggravates hypertension and accelerates atherosclerosis. Microalbuminuria is a sensitive but relatively late marker of diabetic kidney disease. Still, screening of diabetic patients for microalbuminuria is of great importance since there is no other screening test capable of diagnosing diabetic nephropathy at an earlier stage. The description of the genetic substrate of susceptibility to diabetic kidney disease would revolutionize the diagnosis and prevention of diabetic nephropathy. Until then, compliance with therapeutic guidelines outlined in milestone clinical studies of the last years may significantly decrease morbidity, the progression of, and the mortality associated with diabetic kidney disease.

[The place of enalapril in the management of hypertension]. / Az enalapril helye a magasvérnyomás-betegség kezelésében.

In Hungary the use of angiotensin converting enzyme inhibitor enalapril has emerged as one of the most important drugs in the treatment of hypertension. The aim of our study was to evaluate the antihypertensive effect of enalapril of Hungarian production in combination therapy and alone, according to sexes, to the body mass index, among smokers and non smokers as well as non diabetic and in patients with diabetes (IDDM and NIDDM). The diurnal blood pressure values were registered by a 24 hour ambulatory blood pressure monitor. During the 6 weeks of the enalapril therapy (n = 28) both the daytime (141/84 vs. 135/80 mmHg) and the night-time (130/78 vs. 124/72 mmHg) blood pressure values decreased; the increase of diurnal indices during the therapy (SI/DI 6/8% vs. 8/10) reflect the 24 hour long lasting effect of the drug. The body mass index had no influence on the efficacy of treatment. Our results indicate that enalapril manufactured in Hungary is an effective antihypertensive drug both in monotherapy and in combination, in both sexes (especially in men), irrespective of the body weight, in non-smokers and especially in smokers, in insulin dependent and in non-insulin dependent diabetes mellitus alike.

[Hypertensive crisis and its treatment]. / Hochdruckkrise und ihre Behandlung.

Sudden and large increase of the blood pressure may be life-threatening, particularly when they are accompanied by encephalopathy, left-ventricular insufficiency or other complications. The crisis of hypertension shall be treated possibly without loss of time and with energy. If there is the possibility for a permanent control of the patient, the infusion by drops of nitroprusside sodium is the therapy of choice. It at once decreases the blood pressure and is free of side-effects. Diazoxide has the advantage compared with nitroprusside sodium that an intravenous injection decreases the blood pressure for several hours. But the rapid and drastic decrease of blood pressure may occasionally be dangerous in patients with coronary insufficiency and cerebral arteriosclerosis. In certain indications also other medicaments, such as reserpine, alpha-methyldopa, phentolamine, saralasin or nifedipine can be applied. The crisis of hypertension is always to be regarded as an emergency situation, since always irreversible lesions may be appear on the different organs as a sequel of the permanent vasoconstriction and ischaemia.

Mechanism of carotid-occlusion diuresis.

In anaesthesized dogs given large doses of ADH and DOC and subjected to acute left renal denervation, urine flow (V) and sodium excretion (UNaV) rose significantly in response to bilateral carotid artery clamping in both the intact (p less than 0.05) and the denervated kidney (p less than 0.001). This was associated with significant (p less than 0.05) increases of the tubular rejection fraction of sodium (TRFNa) while creatinine clearance (Ccr) remained unchanged. Following a second control period, carotid occlusion was repeated, while perfusion pressure in the left kidney was kept constant by aortic constriction. In this case the diuretic and natriuretic response in the right kidney occurred in the same fashion as previously, and no significant change in V, UNaV, or TRFNa was observed in the left kidney. The amount of free water reabsorbed in the collecting duct (TcH2O) was not consistently altered by carotid occlusion. It is concluded that acute renal denervation augments the pressure diuresis that follows carotid occlusion. The failure of carotid polyuria to occur when renal perfusion pressure is kept constant points to the importance of mechanical factors. Still, a wash-out of the medullary osmotic gradient seems to be an unlikely mechanism.

Body sodium, atrial natriuretic peptide and blood pressure in diabetes mellitus.

Diabetes mellitus (DM) is frequently associated with hypertension for which an independent pathomechanism has been suggested. We studied 26 patients with insulin-dependent (IDDM) and 18 patients with non-insulin-dependent (NIDDM) uncomplicated DM; all patients were in metabolic balance and none of them had hypertension. Exchangeable body sodium (NaE was estimated by isotope dilution, using appr. 1.1 Mbq 24NA. In a subset of 8 IDDM and 8 NIDDM patients atrial natriuretic peptide (ANP) plasma concentration was determined prior to and after the infusion of 2000 ml physiological saline over 2 hr. NaE was significantly increased both in IDDM and NIDDM patients (104.4 +/- 11.4% and 109.9 +/- 8.0% of the normal value for healthy subjects of identical body surface area; p < 0.05 and < 0.001 resp.). Mean blood pressure (MBP) correlated significantly with NaE in both groups (r = 0.364 and r = 0.520; p < 0.05 and < 0.025, resp.) but not in healthy control subjects (r = 0.112; N.S.). Resting ANP levels were not significantly different in IDDM (34.9 +/- 11.3 pg/ml), NIDDM (42.6 +/- 11.7 pg/ml) or control subjects (40.9 +/- 17.2 pg/ml) however the infusion of saline resulted in a significantly greater increase of plasma ANP in the NIDDM patients (to 82.9 +/- 43.2 pg/ml; P < 0.01) than in the controls (55.6 +/- 23.7 pg/ml; P < 0.01) which was associated with a significantly less increase in sodium excretion (UNAV) in the NIDDM patients (+86% vs. 3170%; P < 0.02) indicating down-regulation of ANP receptors in the kidney of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Exchangeable body sodium in normal man: analysis of various frames of reference.

Exchangeable sodium is a reliable measure of body sodium contents. Since fat tissue contains significantly less sodium per unit of weight than other tissues, leanness of an individual may considerably affect exchangeable body sodium. Thus, subjects of different body size can be compared only when body build is considered. To evaluate various frames of reference, we analysed the relationship between exchangeable sodium as determined by isotope dilution and various parameters of body size. Body weight, body height, body surface area, and leanness index correlated significantly with exchangeable sodium, the closest relationship having been obtained with body surface area (r = 0.790; p less than 0.001). When analysing males and females separately (n = 18 and 36, resp.), best parallelism of regression lines was also obtained with body surface area. It is concluded that exchangeable sodium should be referred to unit of body surface area, expressing each individual's value as percent of the normal predicted value calculated from the regression equations y = 1388x + 370 and y = 1554x - 196 for males and females, respectively.

Effects of chronic alpha and beta adrenoceptor blockade with labetalol on plasma catecholamines and renal function in hypertension.

Plasma catecholamines and renal function were evaluated in 18 patients with essential hypertension treated with the alpha and beta adrenoceptor blocking agent, labetalol. Following 6 weeks of labetalol therapy, blood levels of epinephrine and norepinephrine remained unaltered. Glomerular filtration rate and renal plasma flow were decreased similarly by about 20% (P less than 0.025). Tubular rejection fraction of sodium was increased by 36% (P less than 0.001) while sodium excretion was comparable to control conditions. Labetalol's potential to cause a mild reduction in kidney function should be considered, but may have no clinical consequences in most hypertensive patients receiving such treatment. The lack of increased plasma catecholamine levels during therapy supports the concept that labetalol's alpha-blocking potential is limited to post-junctional receptors, leaving the prejunctional feedback control of catecholamine release intact. Moreover, labetalol's blood pressure-lowering mechanism may be largely independent of changes in sympathetic nervous activity.

Production of ouabain by rat adrenocortical cells.

Our aim was to identify which adrenocortical cells produce ouabain and how it is regulated in vitro. With the help of an ouabain radioimmunoassay developed in our laboratory, we found that ouabain is produced both by zona glomerulosa and fasciculata cells. Our results were confirmed by reverse-phase HPLC. ACTH increased ouabain production in both cell types. Angiotensin-II, as well as changes in the potassium concentration of the incubation medium, affected ouabain production only in the zona glomerulosa.

[Correlations between blood pressure, blood volume and plasma renin during therapy with diuretics in essential hypertension. Comparison between the mineralocorticoid antagonist spironolactone and the "loop" diuretic mefruside]. / Beziehungen zwischen Blutdruck, Blutvolumen und Plasmarenin während Diuretikatherapie bei essentieller Hypertonie. Vergleich des Mineralocorticoid-Antagonisten Spironolacton mit dem "Schlefendiuretikum" Mefrusid

35 patients with benign essential hypertension were treated for 6 weeks with high doses of the mineralocorticoid-antagonist spironolactone (400 mg/day), or with the "loop-diuretic" mefruside (mean maximal dose 110 mg/day). Spironolactone caused greater reductions in blood pressure and blood volume and a more marked increase in plasma renin activity (PRA) than mefruside (p less than 0.05). It appears possible that he weaker antihypertensive effect of mefruside may relate partly to its lesser influence on circulatory volume. With both diuretics, mean decreases in blood pressure were greater in patients with low pre-therapeutic PRA than in patients with normal or high PRA. However, the diuretic-induced changes in blood pressure did not correlate with the associated variations in blood volume or PRA. Thus, the increased blood pressure sensitivity to diuretics in patients with low-renin essential hypertension did not appear to be volume or renin-dependent. Under normal conditions, the maintenance of a constant blood pressure during volume depletion may partly depend on compensatory activation of the sympathetic nervous system. Moreover, patients with low-renin essential hypertension have been found to have decreased adrenergic activity. It seems possible, therefore, that the marked blood pressure sensitivity to diuretic treatment in such patients may be the result of an impaired compensatory sympathetic response to sodium and volume depletion. Analysis of the literature suggests that the diuretic furosemide, a structural relative of mefruside, may also have less blood pressure lowering efficacy in patients with essential hypertension than the distally-acting thiazides, chlorthalidone or spironolactone. Consideration of possible differences in the blood pressure reducing potential of certain diuretics thus appears to be necessary in planning the pharmacotherapy of essential hypertension.

Blood pressure, circulating renin and the body sodium/volume state in patients with mild renal failure.

Hypertensive patients with various renal lesions and a mean plasma creatinine of 2mg/100ml showed increases (p is less than 0.05) in mean exchangeable sodium and plasma renin activity, while blood volume was not altered significantly. Patients with mild renal failure and normal blood pressure demonstrated no consistent abnormalities in these parameters. Blood pressure correlated significantly with exchangeable sodium and with the 'sodium-renin' and 'blood volume-renin' products; but not with circulating renin or volume individually. This suggests that subtle abnormalities in the physiological sodium/volume-renin feedback mechanism may occur already in the earliest stages of renal disease and may contribute to the hypertension in such patients.

Pharmacokinetics and pharmacodynamics of mibefradil in hypertensive patients with varying degrees of renal insufficiency.

Mibefradil, the first member of the tetralol derivatives, a new class of calcium antagonists, is used for the treatment of hypertension and angina pectoris. This study was designed to investigate the effect of varying degrees of chronic renal impairment on mibefradil pharmacokinetics and pharmacodynamics. Neither pharmacokinetic nor pharmacodynamic parameters varied as a function of renal status. Additionally, hemodialysis removed only a relatively small fraction of drug from the body. It was concluded that the majority of renal-failure patients will not require a change in mibefradil dosage relative to patients with normal renal function. Following hemodialysis, supplemental mibefradil treatment should not be necessary.

Relationship between exchangeable body sodium and urinary 6-keto-prostaglandin F1 alpha excretion in normal man.

The renal prostaglandins are involved in the regulation of sodium balance. In the present study exchangeable body sodium (NaE) and the urinary excretion of the stable metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) were determined simultaneously in 10 hospitalized healthy individuals. NaE was 1461 +/- 107 mmol/m2 body surface area, or 98.5 +/- 6.9% when expressed as percent of the normal value assessed on the basis of measurements in 54 control subjects. The excretion of 6-k-PGF1 alpha amounted to 68.3 +/- 39.2 ng/4 hr. Statistical evaluation revealed significant correlation between NaE and PGF1 alpha excretion (r = 0.642; p less than 0.05) and between the serum Na concentration and the urinary excretion of 6-k-PGF1 alpha (r = 0.865; p less than 0.001). The obtained results indicate that urinary 6-k-PGF1 alpha excretion, hence the renal synthesis of prostacyclin, are regulated, among other factors, by body sodium stores. The increased production of prostacyclin with expanding sodium space might be regarded as a compensatory response contributing to the renal elimination of excess sodium from the body. The signal to this response could be the serum Na concentration.