Experimental cardiac fibrosis: differential time course of responses to mineralocorticoid-salt administration.

The rapid (1-4 h) responses of epithelial target tissues to mineralocorticoids contrast with the days/weeks apparently required for responses in the cardiovascular system. The present study explores the time course and pattern of early events leading to cardiac fibrosis in the mineralocorticoid-salt rat model. Uninephrectomized rats were given deoxycorticosterone (20 mg, sc, weekly) plus 0.9% NaCl/0.3% KCl to drink and were killed at 2, 4, 8, 16, and 32 d. Type III collagen increased progressively from d 2, and blood pressure from d 4, with 4 and 8 d rats showing marked perivascular inflammatory cell infiltration. Apoptosis was also noted in perivascular areas at 4 and 8 d and in scar areas at 8, 16, and 32 d. Elevation of mineralocorticoid hormone levels inappropriate for salt status thus provokes a series of changes in cardiac vessels and myocytes leading to increased collagen deposition. When mineralocorticoid levels are elevated acutely by bolus injection, changes are discernible after 2 d, in contrast with previous infusion studies in which 3-4 wk were required for measurable changes.

Antithyroid therapy improves bony manifestations and bone metabolic markers in patients with Graves' thyrotoxicosis.

OBJECTIVE: Abnormal bone metabolism in patients with Graves' thyrotoxicosis is well documented, but the precise time-course of its recovery remains poorly understood. The present study was undertaken to clarify longitudinal improvement in bony manifestations, especially in cortical bone, and bone metabolic markers in thyrotoxicosis. DESIGN: Two year prospective follow-up study in patients with Graves' disease. PATIENTS: Ten consecutive patients with Graves' disease (seven males and three females, of mean (+/-SEM) age 39.3 +/- 3.9 years) were enrolled in the study and treated with antithyroid drugs. Thirteen sex- and age-matched patients with the disease in remission served as controls. MEASUREMENTS: Bony manifestations were evaluated both by fine cortical bone striations in the metacarpals on magnified roentgenograms and lumbar bone mineral density (BMD) measurement. Urinary deoxypyridinoline (dPYR) and serum pyridinoline cross-linked telopeptide domain of type I collagen (ICTP) were monitored as markers of bone resorption, as well as serum osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (PICP) and alkaline-phosphatase (ALP) as markers of bone formation. RESULTS: Initial elevated free thyroid hormone levels were normalized within a month of starting therapy. Striation indices of the metacarpals were 1.89 +/- 0.16 before therapy, higher than those of 0.49 +/- 0.12 in the controls (P < 0.0001); the indices gradually decreased to 1.00 +/- 0.20 (12 months) and 0.48 +/- 0.12 (24 months). Lumbar BMD Z-scores increased from -0.22 +/- 0.46 to 0.21 +/- 0.47 (12 months) and 0.68 +/- 0.48 (24 months) (P = 0.0029). Before therapy, urinary dPYR and serum ICTP concentrations were much higher than the control values (dPYR, +553%; ICTP, -396%, P < 0.0001), which declined promptly in the 2nd month. Serum OC, PICP and ALP were also significantly higher than in controls at first (OC, +287%; PICP, +225%; ALP, +196%), and remained elevated until 4 or 8 months. CONCLUSIONS: Bone resorption and cortical bone striations occur in untreated patients with Graves' thyrotoxicosis. The bone resorption rapidly ameliorates after normalization of thyroid hormone levels. In contrast, the accelerated bone formation persists for at least 4-8 months, suggesting positive uncoupling of bone remodelling. This dominant bone formation could result in the improvement in cortical bone striations and the increase in bone mineral density of trabecular bone.

Involvement of arginine vasopressin and renal sodium handling in pathogenesis of hyponatremia in elderly patients.

The present study was undertaken to determine the pathophysiological role of arginine vasopressin (AVP) in elderly patients with hyponatremia, and the efficacy of fludrocortisone acetate in treating their hyponatremia. Eleven hospitalized patients aged 65 years or older whose serum sodium levels were less than 130 mEq/l were examined. The hyponatremic patients included two groups of patients: syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and central salt-wasting syndrome. And 24 healthy, young subjects aged 20 to 34 years, and 24 healthy, elderly subjects age 65 to 80 years were recruited by community announcement. The elderly subjects had decreased urinary concentrating ability and exaggerated response of AVP secretion to osmotic and nonosmotic stimuli, as compared to the young subjects. All the patients had hyponatremia, with the exaggerated urinary loss of Na. Plasma AVP levels were elevated despite hypoosmolality in all the 2 groups of hyponatremic, elderly patients. Plasma renin activity and plasma aldosterone concentrations were low in the patients with SIADH and central salt-wasting syndrome. Fludrocortisone acetate therapy was effective in the patients with central salt-wasting syndrome and 3 patients with SIADH whose hyponatremia remained unchanged after water restriction. Water restriction therapy normalized serum Na levels in only 3 patients with SIADH. These results indicate that AVP is involved in the mechanism for hyponatremia in the elderly patients with SIADH and central salt-wasting syndrome. Severe hyponatremia associated with SIADH and central salt-wasting syndrome responds well to mineralocorticoid therapy. Both the secretion of AVP and renal sodium handling may be involved in the mechanism of action of the disorders. The diagnostic criteria for SIADH in the elderly patients may have to be reevaluated and should be considered to indicate fludrocortisone acetate therapy.

Role of water channel AQP-CD in water retention in SIADH and cirrhotic rats.

We determined whether aquaporin of collecting duct (AQP-CD) is involved in pathogenesis of water retention in rats with experimental models of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and liver cirrhosis. SIADH rats were made by administering 1-desamino-8-D-arginine vasopressin (DDAVP) subcutaneously and providing them with a liquid diet. Serum Na levels decreased to < 120 meq/l on day 2, and hyponatremia persisted throughout the rest of observation period. Six hours after the DDAVP infusion, the expression of AQP-CD mRNA significantly increased by 198%, followed by > 144% increases in its expression during the 14-day observation period. On day 7, the increased expression of AQP-CD mRNA was abolished after the administration of an antidiuretic, nonpeptide arginine vasopressin (AVP) antagonist, OPC-31260, which was closely related to a marked diuresis and a prompt normalization of serum Na levels in SIADH rats. Rats were made cirrhotic by injecting a mixture of carbon tetrachloride and olive oil subcutaneously for 3 mo. The expression of AQP-CD mRNA was increased by 164% in the decompensated cirrhotic rats. The blockade of AVP action by OPC-31260 significantly diminished its expression. These results indicate that water channel AQP-CD plays an important role in water retention in pathological states of SIADH and liver cirrhosis.

Possible pre-Cushing's syndrome due to an adrenal adenoma incidentally discovered.

We demonstrated the functional evaluation of adrenal incidentaloma in 8 patients who had no abnormal finding associated with Cushing's syndrome. Adrenal tumors were incidentally discovered by abdominal echogram in 5 patients and by computed tomography (CT) in 3 patients. Serum cortisol levels and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within normal limits in four of 8 patients. Urinary excretion of free cortisol was also within normal limits except for patient 8. Urinary excretion of 17-OHCS, however, was not suppressed by dexamethasone administration in five of 8 patients. Excretion of urinary 17-OHCS did not increase in response to metyrapone in 3 of 4 dexamethasone-insuppressible patients, but increased in 3 dexamethasone-suppressible ones. Serum cortisol increased in response to exogenous ACTH in all 6 patients examined. 131I-Adosterol accumulation was found in only the tumor side in 7 patients and bilaterally in one patient. Adrenalectomy was done in 7 patients, and microscopic findings showed adrenocortical adenoma. Serum cortisol was significantly suppressed in response to dexamethasone in the post-operative stage in all 7 patients examined. These results indicate that these adrenal incidentalomas seem to have a cortisol over-production which is dexamethasone-insuppressible and ACTH-dependent, and that they can be classified as "Pre-Cushing's Syndrome."

An autopsy case of licorice-induced hypokalemic rhabdomyolysis associated with acute renal failure: special reference to profound calcium deposition in skeletal and cardiac muscle.

A 78-year-old man was hospitalized because of muscular weakness and acute renal failure. He had been taking glycyrrhizin (280 mg/day) for the last 7 years. Hypertension was noted in his history. Serum potassium was 1.9 mEq/l with metabolic alkalosis. There was hyporeninemic hypoaldosteronism. Serum enzymes, including GOT, LDH and CPK were markedly elevated. In addition, serum myoglobin was as high as 46 micrograms/ml with massive myoglobinuria. Oliguria occurred and blood urea nitrogen and serum creatinine rapidly elevated from 20.9 to 87 mg/dl and from 1.3 to 6.7 mg/dl, respectively. Profound calcium deposition was found in the damaged skeletal muscles, including the quadriceps femoris, axillar, neck, and cardiac muscles. These results indicate that licorice-induced pseudoaldosteronism produces hypokalemic rhabdomyolysis, resulting in acute renal failure and profound deposition of calcium into the damaged skeletal and cardiac muscles.

In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats.

The present study was undertaken to determine whether a non-peptide arginine vasopressin (AVP) antagonist (5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra hydro-1H- benzazepine; OPC-31260) antagonizes the antidiuretic action of endogenous and exogenous AVP in conscious rats. OPC-31260, given orally at a dose of 5 mg/kg or higher, increased urinary volume (UV) and reduced urinary osmolality (Uosm) in a dose-dependent manner, in rats acutely denied access to water. Minimal Uosm was obtained 1-2 h after oral administration of OPC-31260. OPC-31260 caused sustained water diuresis for more than 12 h when water was available ad libitum since OPC-31260 (30 mg/kg) reduced Uosm to less than 230 mOsmol/kg H2O, significantly less than the control value of 600 mOsmol/kg H2O. Water deprivation for 24 h increased plasma AVP levels to 7.2 pmol/l and increased Uosm to 2160 mOsmol/kg H2O. In such water-deprived rats, oral administration of OPC-31260 at 100 mg/kg was diuretic; it markedly increased free water clearance and decreased Uosm to 202 mOsmol/kg H2O. In homozygous Brattleboro rats (with inherited AVP deficiency), given free access to water, subcutaneous infusion of the V2 agonist 1-deamino-8-D-AVP (dDAVP) at a rate of 1 ng/h markedly decreased UV to 12.6 from 148.7 ml/day and increased Uosm to 1762 from 231 mOsmol/kg H2O. OPC-31260 (30 mg/kg) promptly increased UV and reduced Uosm to levels similar to those before the administration of dDAVP; repeated OPC-31260 treatment had sustained effects. These results indicate that OPC-31260 is an orally effective non-peptide AVP antagonist to the antidiuretic action of AVP in the conscious rat.

Therapeutic efficacy of the non-peptide AVP antagonist OPC-31260 in cirrhotic rats.

The present study was undertaken to determine whether a non-peptide arginine vasopressin (AVP) antagonist [5-dimethylamino-1-(4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra hydro-1H- benzazepine] (OPC-31260) improves the impaired water excretion in rats with experimental liver cirrhosis. Male Wistar rats weighing 200 to 250 g were injected in an equal volume (4 ml/kg) of carbon tetrachloride and olive oil at an interval of seven days for three months, causing liver cirrhosis with ascites. Control rats were injected with only olive oil. Body weight (body wt) and hematocrit (Hct) were lower in the cirrhotic rats than the control rats (body wt 360.7 vs. 238.5 g, P < 0.01; Hct 46.3 vs. 39.2%, P < 0.01). A water loading test (30 ml/kg) was carried out and 20-minute urine collections were made for three hours. The percent of water load excreted was 62.5% in the cirrhotic rats, a value significantly less than that of 102.1% in the control rats. However, its percent increased to 215.1% after the oral administration of 5 mg/kg OPC-31260 (P < 0.01). Minimal urinary osmolality (UOsm) was 185.5 mOsm/kg H2O in the cirrhotic rats receiving the vehicle, a value greater than the control rats of 125.5 mOsm/kg H2O (P < 0.01). The oral administration of 5 mg/kg OPC-31260 reduced minimal UOsm to 85.2 mOsm/kg H2O in the cirrhotic rats (P < 0.01). Urinary excretion of sodium was lower in the cirrhotic rats than the control rats (87.1 vs. 312.4 microEq/3 hr, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Opposite changes in serum sodium and potassium in patients in diabetic coma.

We studied the changes in serum sodium (Na) and potassium (K) levels in seventeen patients in diabetic ketoacidosis and nine patients in non-ketotic hyperosmolar coma, who had marked hyperglycemia (707.4 +/- 75.6 mg/dl, mean +/- SEM) and dehydration. The disorder characterized two types of alteration. The one group was hyponatremia with hyperkalemia in 17 patients in diabetic ketoacidosis (132.9 +/- 2.0 and 5.7 +/- 0.2 mEq/l), and 4 patients in non-ketotic hyperosmolar coma (125.8 +/- 4.3 and 5.2 +/- 0.5 mEq/l). The other was hypernatremia (162.5 +/- 1.8 mEq/l) with hypokalemia (3.4 +/- 0.2 mEq/l) in 5 patients in non-ketotic hyperosmolar coma. Intensive therapy with insulin and fluid administration improved the diabetic hyperglycemia and associated abnormalities. The vectors showing the normalization of serum Na and K levels was in quite opposite directions between the patients with hyponatremia with hyperkalemia and those with hypernatremia with hypokalemia. The amounts of loss of circulatory blood volume exceeded 20% in three groups of patients, a loss greater in the hypernatremic patients than in the hyponatremic ones. These results indicate that serious body water depletion produces hypernatremia instead of hyponatremia in patients in diabetic coma. The disorder may be caused by the altered distribution of electrolytes between the intra- and extra-cellular spaces.

Thapsigargin increases cellular free calcium and intracellular sodium concentrations in cultured rat glomerular mesangial cells.

We examined whether thapsigargin increases cellular free calcium ([Ca2+]i) and intracellular sodium concentration ([Na+]i) in cultured rat glomerular mesangial cells. 1 x 10(-6) M Thapsigargin increased [Ca2+]i to 244.4 from 86.6 nM, an increase sustained at least during the 15 min observation period. Such an increase in [Ca2+]i was transient in Ca(2+)-free medium containing 1 x 10(-4) M EGTA. An increase in [Ca2+]i by thapsigargin was not altered by 1 x 10(-6) M nicardipine, a L-type Ca2+ channel blocker. Thapsigargin also produced a sustained rise in [Na+]i in a dose-dependent manner. However, preincubation of cells with Ca(2+)-free medium completely blocked the increase in [Na+]i by thapsigargin. These results indicate that thapsigargin increases [Ca2+]i by blocking endoplasmic Ca(2+)-ATPase and enhancing Ca2+ entry, and that the increased Ca2+ influx is triggering an increase in [Na+]i stimulated by thapsigargin per se in glomerular mesangial cells.

Therapeutic efficacy of non-peptide ADH antagonist OPC-31260 in SIADH rats.

The present study was undertaken to determine whether the non-peptide V2 antidiuretic hormone (ADH) antagonist 5-dimethylamino-1[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260) normalized hyponatremia in rats with an experimental syndrome of inappropriate secretion of ADH (SIADH). Rats were administered V2 agonist 1-deamino-8-D-arginine vasopressin (dDAVP) subcutaneously at a rate of 5 ng/hr using an osmotic minipump and a 40 ml/day liquid diet. Serum sodium levels (SNa) and serum osmolality (SOsm) markedly decreased to 119 mEq/liter and 249 mOsm/kg H2O, respectively, 48 hours after the start of dDAVP administration. Hyponatremia persisted in a similar magnitude during the observation period of 14 days. On days 7 to 13 OPC-31260, administered 5 mg/kg per day orally, promptly raised SNa and SOsm to 134 mEq/liter and 282 mOsm/kg H2O in half a day, respectively, followed by the normalization of SNa and SOsm during the rest of the observation period. The cease of administration of OPC-31260 again decreased SNa and SOsm in rats receiving dDAVP. In contrast, SNa and SOsm were within the normal values in rats receiving 0.15 M NaCl, a vehicle for dDAVP, in the presence or absence of OPC-31260. The administration of OPC-31260 promptly caused marked water diuresis on day 7 in the hyponatremic rats receiving dDAVP, namely 5 mg/kg OPC-31260 markedly increased urinary volume and decreased UOsm. These results indicate that there is dilutional hyponatremia in rats receiving dDAVP and 40 ml/day liquid diets, and that OPC-31260 is an effective therapeutic for hyponatremia associated with dDAVP-induced SIADH.

Role of antidiuretic hormone in hyponatremia in patients with isolated adrenocorticotropic hormone deficiency.

We found symptomatic hyponatremia in four elderly patients in which serum sodium (Na) levels ranged from 101 to 122 mEq/l. All 4 patients had low levels of plasma adrenocorticotropic hormone (ACTH), serum cortisol, and urinary excretion of 17-OHCS, and poor responses of ACTH to exogenous insulin and antidiuretic hormone (ADH). Other pituitary hormones were all normal. They were therefore diagnosed as having isolated ACTH deficiency. Plasma ADH was relatively high despite hypoosmolality which was associated with the hyponatremia. Water loading test revealed impaired water excretion and poor suppression of plasma ADH. Replacement with 20-30 mg hydrocortisone completely restored the serum Na level and restored the plasma ADH level to the normal range in all 4 patients. Other factors such as decreased glomerular filtration, enhanced urinary Na loss and decreased Na intake were also included. These results indicate that there is marked hyponatremia and that in the presence of hypoosmolality the sustained secretion of ADH is the key factor in causing the impaired water excretion and hyponatremia in isolated ACTH deficiency.

Hyponatremia and hyperreninemic hypoaldosteronism in a critically ill patient: combination of insensitivity to angiotensin II and tubular unresponsiveness to mineralocorticoid.

A 62-year-old man with pneumonia and left flank pain had a clinical syndrome of hyponatremia, hypotension, dehydration, and high urinary sodium excretion in the presence of a normal glomerular filtration rate. The plasma level of antidiuretic hormone was relatively high despite decreased serum osmolality. Thyroid function and excretion of glucocorticoid and sex steroids were normal. The serum aldosterone level was very low despite elevated plasma renin activity. Angiotensin II failed to stimulate any secretion of aldosterone, despite the occurrence of a progressive rise in blood pressure. On the other hand, rapid ACTH administration increased both serum aldosterone and cortisol. The patient showed no effective response to increased salt intake, but large doses of mineralocorticoid resulted in a normal serum sodium level without dehydration. Subsequently, he suffered cardiac arrest secondary to ventricular tachycardia. Postmortem examination showed well differentiated adenocarcinoma in the left pleura and an intact, histologically normal adrenal zona glomerulosa and kidney. This is the first reported case of a critically ill patient with hyponatremia caused by hyperreninemic hypoaldosteronism possibly due to angiotensin II insensitivity and tubular unresponsiveness to mineralocorticoid.