Peripheral effects of thyroid hormones: Alteration of intracellular Na-concentration,ouabain-sensitive Na-transport,and Na-Li countertransport in human red blood cells

Summary To investigate the effect of thyroid hormones on erythrocyte cation transport systems and intracellular electrolyte content we have measured the activity of Na-K ATPase, Na-Li countertransport, as well as red cell sodium and potassium contents in patients with hyperthyroidism and in euthyroid controls. Intracellular Na- and K-concentrations were determined in erythrocytes washed three times in isotonic MgCl₂ solution. Ouabain-sensitive Na-transport was estimated as the increase of Na before and after addition of ouabain in an erythrocyte suspension in isotonic Na-free medium. Na-Li countertransport was measured according to the method described by Canessa et al. [2]. The patients with hyperthyroidism exhibited a significantly elevated intracellular sodium content as well as a highly increased Na-K ATPase activity. Intracellular potassium content was not altered in the hyperthyroid subjects, but Na-Li countertransport was markedly decreased as compared to the controls.The results indicate that different ion transport systems of the erythrocyte membrane are influenced by thyroid hormones. We suggest that the elevation of Na-K ATPase activity might be due to the increased intracellular sodium concentration which is caused by the diminished countertransport pathway. Furthermore, the activity of Na-K ATPase, Na-Li countertransport, and intracellular sodium content in erythrocytes might be a useful peripheral indicator of thyroid hormone excess.Supported by the Bundesministerium für Forschung und Technologie (MMT 27)     

The antihypertensive effect of captopril in severe essential,renovascular, renal and transplant renovascular hypertension

Summary The acute and long-term (6 months) effects of captopril (C) were studied in 23 patients with previously uncontrolled severe (DBP>120 mmHg) hypertension of different origin: essential (EH)n=10, renovascular (RVH)n=9, and renal (RH)n=4. In addition, four patients were treated with renal transplant artery stenosis and hypertension (TRVH), refractory to conventional therapy. Before treatment supine blood pressure (BP, mmHg) averaged: 205/131 (EH), 204/124 (RVH), 207/132 (RH) and 194/117 (TRVH). All patients received diuretics and other antihypertensive drugs, the dosages of which are expressed in arbitrary equivalent units (U) per day (UD=diuretics; UA=other antihypertensive drugs). Antihypertensive therapy before study:UD: EH 1.6; RVH 1.0;UA: EH 7.3; RVH 5.5. After admission, C dosage was increased from 25 mg to a maximum of 150 mg t.i.d. Antihypertensive treatment was reduced as far as possible. DBP decrease after 25 mg C was related to pretreatment PRA in RVH only. After 3 months of C treatment, BP decreased to 190/116 in EH and 145/89 in RVH (EH vs RVHP<0.01), 158/98 in RH, and 154/90 in TRVH. After 6 months, BP response was maintained in RH and TRVH. BP increased slightly in RVH to 158/102 mmHg, mainly because of impaired renal function in three patients with bilateral renovascular disease. In EH,BP decreased to 167/109, since three non-responders were taken out of the group. After 6 months, EH still received higher dosages of antihypertensive drugs than RVH. Acute and chronic hypotensive effects of C were not significantly correlated. Side-effects occurred in five patients: skin rash and pruritus [2], taste disturbances [1], proteinuria [1], and acute renal failure in one patient with TRVH. In our hands, captopril in combination with diuretics was significantly more potent in severe RVH than in EH. Dosages and side-effects of other antihypertensive drugs could be markedly reduced in most patients, which may improve long-term drug compliance.     

Red-cell lithium-sodium countertransport and renal lithium clearance in hypertension

Red-cell lithium-sodium countertransport is increased in patients with essential hypertension. It has been proposed that sodium-hydrogen ion exchange in the brush border of the renal proximal tubules is analogous to red-cell countertransport. To investigate the rate of sodium reabsorption by the proximal renal tubules in hypertension, we measured lithium clearance (a measure of proximal tubular reabsorption of sodium), as well as red-cell countertransport, in 14 patients with untreated essential hypertension and in 31 controls. As a group, the hypertensive patients had a higher average (+/- SEM) rate of red-cell countertransport (0.378 +/- 0.030 mmol of lithium per liter of cells per hour, P less than 0.01) and a lower renal fractional lithium clearance (13.96 +/- 0.69 percent, P less than 0.01) than normotensive subjects (0.317 +/- 0.015 mmol of lithium per liter of cells per hour and 17.75 +/- 0.81 percent, respectively). Within the normotensive group, subjects with hypertension in at least one first-degree relative had significantly lower fractional lithium clearances than subjects with no hypertensive relatives (15.37 +/- 0.84 percent vs. 19.06 +/- 1.07 percent, P less than 0.05). We conclude that hypertensive patients have heightened proximal tubular reabsorption of sodium and that red-cell countertransport is a marker of the renal abnormality. Enhanced proximal tubular sodium reabsorption may precede the development of essential hypertension.     

A biometrical study of the relationship between sodium-lithium countertransport and triglycerides

We addressed the question: Is there evidence that allelic variation in a single unmeasured gene that has a large effect on maximal activity of erythrocyte sodium-lithium countertransport (Na-Li CNT) also has pleiotropic effects on variation in plasma triglyceride levels? Complex segregation analysis models that included plasma triglyceride levels as a covariate were considered as explanations for interindividual variation in Na-Li CNT. A sample of 711 healthy adults from 254 pedigrees enrolled in the Rochester Family Heart Study was selected for this study. The majority of the pedigrees supported the hypothesis that variations in a single unmeasured non-transmitted environmental factor have large effects on the Na-Li CNT distribution. Only gender-specific first-order covariate parameters were necessary in the complex segregation models suggesting that the form of the relationship between Na-Li CNT and plasma triglyceride level was not influenced by variation in the inferred environmental factor with large effects. Stratification of the sample by this inferred environmental factor resulted in three classes of individuals with significant differences in the distributions of coronary heart disease risk factor traits, as well as interindividual variation in both Na-Li CNT and plasma triglyceride levels. These results, along with other observations from the Rochester Family Heart Study sample, emphasize the complex and multifactorial nature of the causes of interindividual variation in Na-Li CNT. Our study further suggests that new research strategies are needed for studying the relationships between genetic and environmental variation and variation in quantitative traits such as Na-Li CNT that have been identified as risk factors for hypertension.     

Pathogenesis of arterial hypertension in diabetes mellitus]

To investigate pathogenesis of arterial hypertension in diabetes mellitus, the authors measured parameters of central and peripheral hemodynamics, basal renin levels, angiotensin, aldosterone, kallikrein-kinin system. The results were analysed with regard to hypertension type: essential (EH), atherosclerotic (AH) and nephrogenic (NH). Hypokinetic circulation, defected vascular elasticity, activation of renin-angiotensin-aldosterone system and hypoactivity of kallikrein-kinin system were characteristic of EH and AH. Most pronounced changes in peripheral hemodynamics and hypoactivity of depressor kallikrein-kinin system were seen in NH.     

Proton magnetic resonance spectroscopic changes of the primary motor cortex and supplementary motor area in hemiparetic patients with corticospinal tract injury due to deep intracerebral hematoma

This study was conducted to investigate the metabolic changes in the motor and motor association cortices following axonal injury in the internal capsule that was caused by deep intracerebral hematoma. Using proton magnetic resonance spectroscopy (1H MRS), the authors studied the primary motor cortices (M-1) and supplementary motor areas (SMA) of 9 hemiparetic patients with documentable hemiparesis of varying severity, and we studied 10 normal volunteers as controls. To measure the M-1 and SMA biochemical changes, 4 separate single volumes of interest (VOIs) were located bilaterally in the affected and unaffected hemisphere (AH and UH). 1H MRS provided a neuronal and axonal viability index by measuring levels of N-acetylaspartate (NAA) and creatine/phosphocreatine (Cr). The M-1/SMA NAA/Cr ratios of the AH and UH in patients, and the AH and normal volunteers were compared. The NAA/Cr ratios of the M-1 and SMA in AH, and the SMA in UH were significantly lower than those of normal volunteers. These 1H MRS findings indicate that axonal injury in the descending motor pathway at the level of internal capsule could induce metabolic changes in the higher centers of the motor pathway.     

Hyperplasia of renin-containing cells in a malignant pheochromocytoma: an immunohistochemical and semiquantitative study

The renin-containing cells in the kidneys of a patient with malignant pheochromocytoma were investigated immunohistochemically. Elevated plasma renin and catecholamine levels were detected during the clinical course. Remarkable hyperplasia of renin-containing cells was observed in the afferent arterioles and interlobular arteries. Semiquantitative assessment was performed to compare this case with cases of renovascular hypertension, with one case of malignant nephrosclerosis, and with six cases without hypertension. The grade of hyperplasia of renin-containing cells in pheochromocytoma was similar to that in renovascular hypertension and was different from that observed in control cases. Histologic examination of the kidneys revealed neither stenosis of the renal arteries nor ischemic changes of glomeruli. Direct stimulation of renin-containing cells by catecholamines is suggested as the cause of the hyperplasia. This is the first morphologic demonstration of hyperplasia of renin-containing cells in pheochromocytoma.     

Measurement of norepinephrine and 3,4-dihydroxyphenylglycol in urine and plasma for the diagnosis of pheochromocytoma

We compared the value of plasma samples with that of 24-hour urine samples in identifying patients with pheochromocytoma among those with hypertension. We employed specific gas chromatographic-mass spectrometric analysis of both urine and plasma for simultaneous assay of norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG). The study population consisted of 1086 patients with hypertension, among them 25 patients with proved pheochromocytoma. Reference ranges for free norepinephrine and DHPG in plasma and urine were established. Measurement of free norepinephrine in 24-hour urine samples provided the best index of a pheochromocytoma. This technique had 100 percent sensitivity and 98 percent specificity among 1192 urine samples, as compared with 82 percent sensitivity and 95 percent specificity among 358 plasma samples. Simultaneous measurement of norepinephrine and DHPG in urine further improved specificity (to 99 percent), but the use of the ratio of norepinephrine to DHPG reduced sensitivity (to 95 percent), since some patients with pheochromocytoma secrete large amounts of DHPG. We therefore recommend measurement of 24-hour urinary levels of free norepinephrine for the diagnosis of pheochromocytoma and suggest that simultaneous analysis for DHPG may sometimes prove useful in reducing the rate of false positive results.     

Inhibition of angiotensin conversion and prevention of renal hypertension.

Renal artery constriction in the unilaterally nephrectomized, trained dog, with maintained renal arterial hypotension, produces a prompt increase in systemic renin activity and blood pressure. The hypertension normally induced by renal artery stenosis is prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro (SQ 20, 881), which blocks conversion of angiotensin I to angiotensin II. Constant intravenous infusion of the inhibitor over several days of renal artery constriction prevents the development of chronic renovascular hypertension. Furthermore, a single injection of the nonapeptide restores blood pressure to normal in the early phase of renovascular hypertension, but becomes progressively less effective as salt and water retention occurs in the chronic stage when plasma renin activity returns to control levels. These data provide strong evidence that the renin-angiotensin system is responsible for the initiation of renovascular hypertension in the one-kidney Goldblatt dog, but that other factors become increasingly important in chronic renovascular hypertension.     

Long-term results in 64 patients operated upon for pheochromocytoma

During the years 1956-1982, 64 pheochromocytoma patients were operated upon without mortality. Twenty-eight patients had sustained hypertension and 29 paroxysmal hypertension only. In two patients high blood pressure was not related to pheochromocytoma and five subjects were normotensive. In two women the pheochromocytoma demonstrated malignancy by widespread metastases. Sixteen patients also had neuroectodermal manifestations other than pheochromocytoma. Preoperatively, heart disease was found in most of the hypertensive patients aged 50 years or more at operation, but was uncommon in the others. In these subjects, heart disease persisted after surgery. Young subjects with sustained hypertension were not less affected by preoperative cerebrovascular accidents than older subjects. After surgery, hypertension persisted in 12 patients, and was easily controlled by drug therapy in eight. Nine patients died 7 months-18 years after surgery. In no case was the death directly associated with the pheochromocytoma disease. Three died from other neuroectodermal abnormalities. The 55 surviving patients have been followed up for a mean of 12 years after surgery. During the observation time the survival of the pheochromocytoma patients was similar to that of the normal population. At the end of the study, 44 out of the 55 surviving patients were free from symptoms.     

Results of surgery and percutaneous transluminal angioplasty in renovascular hypertension

The results of the treatment with surgery and percutaneous transluminal angioplasty of the renal artery were evaluated in 63 adult patients of both sex, from 16 to 60 years old with renovascular hypertension due to fibromuscular dysplasia in 48 and to atherosclerosis in 15. The stenosis of the renal artery was unilateral in 47 patients and bilateral in 16. The surgical procedures more used were the aorto-renal bypass with saphenous vein in 22 patients and unilateral nephrectomy in 16. From 41 patients treated with surgery, the arterial hypertension was cure or improved after one year in 30 (73.1%). From 22 patients treated with angioplasty, cure or improved was obtained in 17 (77.2%). Satisfactory results were obtained in patients with fibromuscular dysplasia and unilateral stenosis, and poor results in atherosclerosis and bilateral stenosis, with both methods. It is concluded, that surgery and angioplasty are satisfactory therapeutic methods in the renovascular hypertension, principally when is unilateral and due to fibromuscular dysplasia.     

Renovascular hypertension--diagnosis and treatment

The approach and treatment of renovascular hypertension are presented. The study include 65 patients with severe arterial hypertension (31 men and 34 women), mean age 52 years, 26 of them with renovascular hypertension. Along with the usual diagnostic work-up, renal angiography using Seldinger method and renin measurement were performed in all patients through renal vein. Twelve patients underwent renal artery dilatation (PTRA), six patients kidney autotransplantation, and the rest were treated by medications. In nine patients, complete cure or improvement was achieved by PTRA, whereas unsuccessful renal artery dilatation was recorded in three patients. Surgical therapy for renovascular hypertension was used in six patients and proved successful. It is concluded that the earliest possible detection of renovascular hypertension is of utmost importance because this form of arterial hypertension is one of the most common potentially curable types of secondary hypertension. Concerning the methods of treatment, their invasiveness, and differences between various therapeutic procedures, it is important to make an algorithm of treatment for each individual patient.     

Measures of clinical efficacy. The value of case finding in hypertensive renovascular disease.

An attempt was made to discover the difference in outcomes between treating all patients with essential and renovascular hypertension by drug therapy independent and ignorant of etiologic classification and identifying the patients with renovascular disease and operating on them. Outcomes were categorized as well without complications of hypertension, alive but suffering from a related morbid illness such as coronary or cerebral arterial disease, and dead from the complications of diagnosis, surgery or high blood pressure. The identification and surgical treatment of hypertensive renovascular disease resulted in an incremental benefit in morbidity over blind antihypertensive medical therapy only when the compliance with medical treatment was about 50 per cent or less (the rate suggested for most patient populations). The study underscores the extent to which the quantitative efficacy of diagnositc and therapeutic procedures depends not only on the inherent risks and benefits but also on related social and medical factors.     

Long-term effect of captopril on kidney function in various forms of hypertension

Summary To study long-term effects of captopril on renal function in patients with various forms of severe hypertension, serum creatinine values were monitored in 76 patients under captopril therapy over a period of up to 3 years. Three different groups were formed: (1) patients with essential hypertension (n=37); (2) patients with renovascular hypertension (n=20); (3) patients with renal parenchymatous hypertension (n=19). In each of the three groups reduction in blood pressure was accompanied by increases in serum creatinine. However, both changes were more pronounced in patients with renovascular hypertension. In this group only the rise in creatinine was statistically significant and showed a slight progression with duration of captopril treatment. Group specific analysis revealed that the increase was smaller in patients with unilateral (n=16) renovascular disease than in those with bilateral (n=4) involvement, but in the former it was still significantly higher than in patients with essential or renal parenchymatous hypertension. Separation of patients according to the underlying disease of renovascular hypertension showed that renal function deteriorated less in patients with arteriosclerotic origin (n=10) than in those with fibromuscular dysplasia (n=8). Statistical evaluation of subjects with renovascular and essential hypertension still revealed significant differences in creatinine when the patients with initial plasma renin activity (PRA) below and above 6 ng/ml·3 h were compared separately. A significant correlation (r=0.73;P<0.05) between blood pressure reduction and creatinine changes was obtained only for patients with renovascular hypertension. Finally, in all three groups of patients creatinine changes were statistically independent from daily dosages of captopril. From these data we conclude that sustained impairment of kidney function by captopril is mainly restricted to patients with renovascular hypertension and possibly results from the combined effects of low renal perfusion pressure and interference with intrarenal regulation of glomerular filtration rate by a postulated angiotensin-II-mediated mechanism.Dedicated to Prof. W. Siegenthaler on the occasion of his 60th birthday     

Functional state of the adrenals in various forms of arterial hypertension]

The study of structural changes and changes of the aldosterone content (AC) in the surgically removed adrenals of patients with different clinical variants of combination of the arterial hypertension (AH), low--renin hyperaldosteronism and space--occupying lesions in the adrenals found by CT was carried out. In 15 of 20 patients after adrenalectomy the diagnosis of the primary aldosteronism (PA) was established, in 4 cases diagnosis of the hypertension, 2B degree, and in one case the diagnosis of Cushing disease. The functional state was evaluated according to AC in the adenomas and macronodes and in the adjacent cortex as well as by nuclei size of cells producing aldosterone. The aldosterone hyperproduction was shown to be associated with local adenoma in some cases and with hyperactive cortex in the others this being reflected in the course of AH and in the adrenalectomy hypotensive effect.     

Endothelial function in patients with arterial hypertension and impaired uric acid metabolism

The aim of the study was to investigate endothelial function in patients with arterial hypertension and impaired uric acid metabolism in comparison with patients having arterial hypertension and normal uric acid metabolism. 46 patients aged 32-56 yr with grade I-II AH were included in the study. A group of 36 patients (27 male, 9 female) presented with AH and impaired uric acid metabolism (hyperuricemia), the control group included 10 patients with AH and unaffected uric acid metabolism. Inclusion criteria in the two groups were identical. Endothelial dysfunction was documented in all patients and confirmed by increased levels of serum endothelin-1 and microalbuminuria, qualitative and quantitative changes in the intima-media complex and its thickening. These changes were much more pronounced in patients with hyperuricemia It is concluded that impaired uric acid metabolism in patients with AH leads to rapid onset and progression of endothelial dysfunction. This fact should be taken into consideration by doctors practicing antihypertensive treatment and for the evaluation of cardiovascular risks.     

Interrelationships between sodium clearance,plasma aldosterone,plasma renin activity,renal hemodynamics and blood pressure in renal disease

Summary This study was designed to evaluate the role of aldosterone, glomerular filtration and blood pressure on sodium excretion in renal disease. Sodium clearance (C_Na), plasma aldosterone (PA), plasma renin activity (PRA), glomerular filtration rate (GF), paraaminohippurate clearance (C_PAH) and blood pressure were measured simultaneously in 19 normal subjects, 38 patients with benign essential hypertension, 3 with renal artery stenosis, 48 with chronic glomerulonephritis, 20 with the nephrotic syndrome, 24 with tubulo-interstitial disease and 21 with a renal homograft.C_Na was significantly depressed in patients with the nephrotic syndrome. Mean PA and PRA were increased in renal artery stenosis, but within the normal range in the other groups. C_Na correlated inversely with PA in all groups but one (tubulo-interstitial disease). C_Na correlated directly with GF in the nephrotic syndrome and with the mean blood pressure (mBP) in chronic glomerulonephritis and tubulointerstitial disease. PA correlated directly with PRA and inversely with GF or C_PAH in most groups.It is concluded that PA is an important determinant of the basal natriuresis in renal disease with the exception of tubulo-interstitial nephropathies. In the nephrotic syndrome sodium retention is largely determined by the interaction of PA and GF. In chronic nephropathies, but not in benign essential hypertension, the fractional sodium excretion is partly blood pressure-dependent. Impairment of renal function is often accompanied by a rise in PA.     

Arterial hypertension in renal amyloidosis (a clinico-morphological analysis)

The incidence of arterial hypertension (AH) in patients with renal amyloidosis varied with its stage. Thus, AH was encountered in 13% of cases with renal amyloidosis at the proteinuric stage, 15% of those at the nephrotic stage, and 53% of those at the azotemic stage. One determinant of AH at the first two of these stages appears to have been damage to the antihypertensive system of the renal medulla, while the increased rate of AH at the azotemic stage was found to be associated with sodium retention in the body. AH in renal amyloidosis is an unfavorable prognostic factor, for it is conducive to amyloid shrinkage of the kidneys and to chronic renal failure.     

Pathogenesis and etiology of essential hypertension: role of dietary carbohydrate

The development of essential hypertension (EH) is proposed to be the result of a cascade of metabolic alterations, with high insulin levels/hyperinsulinemia and an abnormal reaction to the vasodilatory effect of insulin as the initiating factors. It is well established that insulin causes vasodilatation of peripheral resistance vessels. In normal subjects, this insulin-induced vasodilatation and decrease of the peripheral vascular resistance (PVR) is compensated by an SNS-mediated re-vasoconstriction in order to avoid hypotension, with the net effect of a slight decrease in blood pressure and no significant effect on peripheral vascular resistance. In contrast, in genetically predisposed subjects, prone to the development of essential hypertension, the insulin-induced vasodilatation is compensated by an increased heart rate and cardiac output (to avoid hypotension), mediated by an abnormal sympathetic overactivity, (characterised by high norepinephrine spillover rates and (frequently) a hyperdynamic circulation), while the PVR remains low during the early phase of developing EH. During the course of chronic hypertension, the SNS-overactivity leads to progressive trophic alterations of vessel walls, and structural and functional vascular remodeling, with narrowing of arterial resistance vessels and an increasing PVR. Vascular remodeling and lumen narrowing not only affect peripheral resistance vessels, but also kidney vessels. Narrowing and decreased distensibility of preglomerular kidney vessels lead to chronic activation of the Renin-Angiotensin-Aldosterone-System, with reinforcement and fixation of hypertension. High-glycemic index nutrition is suggested to play a key role in the etiology of hypertension: The chronic stimulus of pancreatic beta-cells due to high-glycemic index nutrition may cause cell hypertrophy and dysfunction, resulting in postprandial hyperinsulinemia, and -- in susceptible subjects -- the development of EH. Since significant evidence suggests that hyperinsulinemia also represents a key factor for the development of obesity, insulin resistance and the metabolic syndrome, the well-known common association of EH and these metabolic alterations becomes quite understandable.     

Endometrial hyperplasia and the risk of progression to carcinoma

The primary presenting symptom of endometrial neoplasia is abnormal uterine bleeding, which typically prompts an endometrial biopsy to rule out carcinoma. Approximately 70% of women with abnormal uterine bleeding are diagnosed with benign findings and 15% are diagnosed with carcinoma. The remaining 15% receive a diagnosis of endometrial hyperplasia (EH), which includes a broad range of lesions, from mild, reversible proliferations to the immediate precursors of carcinoma. The widely used World Health Organization (WHO) system classifies EH according to four combinations of glandular crowding and nuclear atypia: simple (SH), complex (CH), simple atypical (SAH), or complex atypical hyperplasia (CAH), although the two forms of atypical hyperplasia (AH) are often collapsed into one category. Diagnoses of EH raise three issues. First, the low interobserver reproducibility—less than 50% in almost all studies—hinders the ability of WHO-based classification to effectively guide clinical management. Second, approximately 50% of women diagnosed with AH have concurrent carcinoma. Not surprisingly, most women with AH undergo hysterectomy as primary treatment, but non-surgical management can be effective. Third, data on progression risks for women with EH who retain their uterus are extremely limited. Emerging data indicate the long-term risk among women with SH or CH is less than 5%, but the risk among women with AH is approximately 30%. These data highlight priority areas for future research, such as increasing the diagnostic reproducibility of EH, improving the discrimination between AH and carcinoma, and identifying biomarkers to stratify risks or serve as indicators of response to clinical treatment.