Ultrastructural evidence of thyroid damage in amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis occurs in 2-12.1% of patients on chronic amiodarone treatment. In most cases its pathogenesis is related to iodine overload in the presence of preexisting thyroid abnormalities, such as multinodular or diffuse goiter or autonomous nodule. A minority of patients show apparently normal glands or pictures of non-autoimmune thyroiditis. However, there is recent evidence of a direct toxic effect of amiodarone, with consequent release of iodothyronines into the circulation. We report a patient with amiodarone-induced thyrotoxicosis with toxic thyroid effects demonstrated by electron microscopy in a fine-needle aspiration biopsy. There were three main pathologic findings: multilamellar lysosomal inclusions, intramitchondrial glycogen inclusions--both ultrastructural findings indicating thyroid cell damage--and a microscopic morphological pattern of thyroid cell hyperfunction. No inflammatory changes were found. Plasma thyroglobulin levels were high. The patient proved to be a non responder to simultaneous administration of methimazole (starting dose 30 mg/day) and potassium perchlorate (1000 mg/day for 40 days), while still taking amiodarone, thus providing evidence against a possible pathogenetic role of iodine overload. Dexamethasone (starting dose 3 mg/day) was added to methimazole. After three months euthyroidism had been restored and plasma thyroglobulin level substantially decreased. Subsequent subclinical hypothyroidism developed, which persisted after stopping antithyroid treatment and required substitution treatment with levothyroxine. In view of the primary role of lysosome function in the proteolysis of thyroglobulin molecules and of the energy-requiring carrier-mediated transport of monoiodotyrosine across the lysosomal membrane for iodine salvage and reutilization, we suggest that the pathological lysosomal and mitochondrial changes observed could be an ultrastructural marker for subsequent hypothyroidism in amiodarone-induced thyrotoxicosis. Our observations suggest the usefulness of ultrastructural thyroid evaluation and serial plasma thyroglobulin determinations to thoroughly evaluate the underlying pathogenetic mechanisms in amiodarone-associated thyrotoxicosis with apparently normal thyroid glands. Moreover, more knowledge of its pathogenesis could improve both prognostic stratification and treatment guides.

Alterations in vasopressin regulation in Alzheimer's disease.

A decreased concentration of vasopressin (AVP) in the plasma of patients with Alzheimer's disease has been shown recently and suggests damage to hypothalamic neurosecretory cells. To verify this, osmolar and hypotension (sodium nitroprusside) stimulations on AVP release were applied. The effect of metoclopramide, a powerful stimulator of AVP, was also assessed. Patients with Alzheimer's disease released AVP normally after hypotension. However, AVP response to osmotic stimulation was altered in eight out of 10 patients, owing to low osmoreceptor sensitivity and/or high threshold. Metoclopramide increased AVP in controls but not in patients. Normal AVP response to hypotension in patients with Alzheimer's disease makes it unlikely that there is a significant anatomical loss or damage of hypothalamic neurosecretory cells. Alterations in osmoreceptor function and AVP unresponsiveness to metoclopramide point to damage in the control of AVP release in Alzheimer's disease.

Osmotic and nonosmotic control of vasopressin release in the elderly: effect of metoclopramide.

The study was undertaken to define the relationships between the arginine vasopressin (AVP) response to a pressure-volume stimulus (upright posture test), an osmolar challenge, and metoclopramide injection (20 mg, iv) in normal young and elderly subjects. Besides confirming previous findings of increased AVP responsiveness to osmolar challenge and reduced AVP responsiveness to upright posture in the elderly, we found that metoclopramide stimulated AVP release in both young [from 1.09 +/- 0.05 (mean +/- SD) to 1.77 +/- 0.05 pmol/L; P less than 0.05] and elderly subjects (from 1.54 +/- 0.18 to 4.73 +/- 1.82 pmol/L; P less than 0.01). The response was much greater in the elderly (P less than 0.01). The AVP responses to upright posture and metoclopramide were inversely correlated (r = -0.77; P less than 0.01), suggesting that the elderly have increased sensitivity to stimuli, such as metoclopramide, to counteract their reduced sensitivity to baroreceptor stimulation of AVP release.

Metoclopramide increases vasopressin secretion.

The possibility that metoclopramide (MCP), a potent stimulator of aldosterone secretion, might influence vasopressin secretion in man was studied. MCP (10 mg, iv) increased plasma vasopressin (mean +/- SD) from 1.3 +/- 0.1 to 2.4 +/- 0.1 pg/ml at 10 min and to 2.65 +/- 0.1 pg/ml at 20 min (P less than 0.01) in 10 recumbent normal subjects. No changes in plasma osmolality or peripheral hemodynamics, which might have accounted for the increase in vasopressin, were found. Sulpiride (100 mg iv), haloperidol (2 mg, iv), and domperidone (20 mg, iv), three chemically unrelated antidopaminergic agents, as well as TRH (200 micrograms, iv), failed to modify plasma vasopressin, thus suggesting that the MCP effect on vasopressin is not linked to its antidopaminergic and/or PRL-releasing properties. MCP also was effective in releasing vasopressin in 5 dehydrated subjects, in whom plasma vasopressin increased from 1.9 +/- 0.2 to 3.1 +/- 4 pg/ml (P less than 0.05), and in 5 subjects during steady state water diuresis, in whom free water excretion decreased from 9 to 1 ml/min (P less than 0.01) and plasma vasopressin increased from 0.3 +/- 0.1 to 1.2 +/- 0.2 pg/ml (P less than 0.05). No changes in either vasopressin secretion or free water excretion occurred in 4 patients with severe central diabetes insipidus. These results suggest that MCP stimulates the release of biologically active vasopressin in man.

Alterations in norepinephrine content and beta adrenoceptor regulation in myocardium bordering aneurysm in human heart: their possible role in the genesis of ventricular tachycardia.

On the assumption that alterations in the adrenergic system may play a role in generating ventricular tachycardia in patients with myocardial post-infarction apical aneurysm, we evaluated norepinephrine concentration, number and affinity of both beta 1 and beta 2 adrenoceptors in perianeurysmatic tissue in twelve patients operated upon for congestive heart failure and recurrent sustained ventricular tachycardia. Concentration of norepinephrine in perianeurysmatic tissue was 0.1 +/- 0.05 micrograms g-1 tissue (n = 8), this value being much lower than that found in papillary muscle (n = 10) from patients with mitral valve stenosis (0.8 +/- 0.02 micrograms g-1 tissue) (P less than 0.01). The total number of beta adrenoceptors (71.4 +/- 7.8 v. 48.0 +/- 5.1 fmol mg-1 protein; P less than 0.01) and the percentage of beta 1 subtype were found to be higher in perianeurysmatic tissue (approximately 90%) than in papillary muscle (approximately 68%). Out of twelve patients with aneurysm, beta 2 adrenoceptors had considerably decreased in three patients and were absent in the remaining nine. Decrease in the neuronally released norepinephrine associated with contrasting behaviours of beta 1 and beta 2 adrenoceptors suggests the presence of a profound alteration in the sympathetic innervation of the perianeurysmatic myocardial tissue that may contribute to the genesis of sustained ventricular tachycardia in patients with postinfarction apical aneurysm.

Indapamide in the treatment of hypertension in non-insulin-dependent diabetes.

The antihypertensive effect of indapamide, a new thiazide derivative, has a low diuretic effect and a primary action on vascular smooth muscle. It was evaluated in a series of 20 patients with non-insulin-dependent diabetes (age range 47-75 years) who had arterial hypertension of mild to moderate degree treated with hypoglycemic agents and/or diet. Indapamide, 2.5 mg, was given as a single daily dose for 6 months. A statistically significant reduction of systolic and diastolic pressures was observed in both supine and upright positions. This decrease was significant beginning in the first month of therapy (p less than 0.001). No significant modifications of fasting glycemia, postprandial glycemia, and glycosylated hemoglobin were noted. No significant changes were observed in serum sodium, potassium, chloride, calcium, and uric acid. Indapamide is an effective and practical treatment of hypertension of mild to moderate degree in patients with diabetes. The absence of effect on glucose metabolism makes it an especially interesting drug.

Effects of potassium supplementation on insulin binding and insulin action in human obesity: protein-modified fast and refeeding.

To investigate the role of potassium deficiency in the development of glucose intolerance during caloric deprivation, potassium balance was maintained within normality with oral potassium supplementation in a group of obese subjects who underwent protein-modified fast and the results of the study of carbohydrate metabolism (oral glucose test, insulin receptors on monocytes and peripheral glucose utilization as assessed by euglycaemic clamp) were compared with those obtained in a group of obese subjects admitted to protein-modified fast without potassium supplementation. Caloric deprivation without oral potassium supplementation was followed by a negative potassium balance and a decrease of serum potassium levels; a decrease of the peripheral levels of insulin along with an increase in insulin receptors and a striking reduction of peripheral glucose utilization were also observed. The maintenance of normal potassium balance and normal serum potassium levels with oral potassium-chloride supplementation was associated with higher peripheral levels of insulin (P less than 0.01) and improvement of peripheral glucose utilization (P less than 0.01) whereas the binding of insulin to monocytes was unchanged. The data suggest that potassium depletion during protein-modified fast causes a decrease of the peripheral levels of insulin and a resistance to insulin action at the postreceptors sites which is reversed by potassium supply.

Effects of metoprolol and propranolol on glucose tolerance and insulin secretion in diabetes mellitus.

Twenty-two hypertensive diabetic patients were admitted to a double-blind, within-patient study, and treated with propranolol 80 mg and metoprolol 100 mg twice daily for 4 weeks according to a cross-over design. Dosages of the two drugs such as to induce comparable cardiovascular effects, did not induce relevant changes of fasting blood glucose levels in patients receiving the oral hypoglycaemic agent glibenclamide (group 1), insulin (group 2) or diet alone (group 3). Glucose tolerance, assessed with a 75 g oral load, was however decreased by propranolol, and not by metoprolol in the glibenclamide-treated group. Glucose-induced insulin secretion was reduced by propranolol and not by metoprolol both in the group treated by diet alone and in the glibenclamide-treated group. It is concluded that cardioselective metoprolol seems to be more suitable than the non-selective propranolol in the treatment of arterial hypertension in diabetic subjects, particularly when sulfonylureas are being used as hypoglycaemic agents.

In vitro steroidogenic properties of FK 33 824, a stable analog of methionine-enkephalin. Opiate-dopamine interaction in the control of aldosterone production.

The steroidogenic properties of a stable analog of the endogenous opioid methionine-enkephalin, FK 33 824, were studied with calf adrenal glomerulosa cells and its effects were compared to those of angiotensin II (A II) and metoclopramide. Metoclopramide, A II, and FK 33 824 induced dose-related increases in aldosterone production. The order of potency in stimulating aldosterone was A II, FK 33 824, metoclopramide. Metoclopramide and FK 33 824 did not increase cortisol production. The response to A II but not to FK 33 824 was inhibited by equimolar concentrations of (Sar1 Ala8) antagonist analog of AII (saralasin acetate). By contrast in the presence of equimolar concentrations of naloxone, an opioid receptor antagonist, FK 33 824-induced aldosterone production was markedly inhibited while the response to A II was unchanged. Increases in cAMP accompanied the steroidogenic response to ACTH but not to A II or FK 33 824. Dopamine at physiological concentrations (10(-10) M) inhibited FK 33 824-induced aldosterone production. These results suggest that FK 33 824 is an aldosterone secretagogue and that it initiates steroidogenesis by mechanisms similar to those of A II. However the inability to block its effect with a specific antagonist of A II provides evidence for its action on a separate site.

Chlorpropamide-alcohol flushing in non insulin-dependent diabetes: prevalence of small and large vessel disease and or risk factors for angiopathy.

One hundred and eight non insulin-dependent diabetics were tested for alcohol flushing after chlorpropamide administration (CPAF test). The overall prevalence of patients who flushed at the first challenge was 32%. However, nearly half of them still flushed after alcohol administration, when placebo was given instead of chlorpropamide, so that the prevalence of 'true' flushers was only 17%. Even though the distribution of retinal lesions was similar in 'true' flushers and in non flushers, severe loss of visual acuity was confined to the non flushers and aspecific flushers. The frequency of pathological ECG findings and of peripheral pulse reduction or abolition was significantly higher in the non flushers and aspecific flushers. Blood pressure, serum lipids and hemostatic parameters were similar in the two groups, and therefore do not explain the differences in prevalence of lesions. This study confirms the previous findings of a lower prevalence of large vessel lesions in flushers; however, the prevalence of 'true' CPAF phenomenon in our out-patient population appears to be much lower than previously reported.

Influence of two non-steroidal anti-inflammatory drugs on lipolysis and on plasma post-heparin lipoprotein lipase activity in normal man.

Indomethacin 50 mg i.v. or p.o. and diclofenac sodium 50 mg p.o. produced a prompt and significant increase in plasma free fatty acid concentration. In 10 subjects who took indomethacin 150 mg/d p.o. for 3 days, plasma post-heparin lipoprotein lipase activity was also significantly increased. The same effect occurred in 9 subjects treated for 3 days with diclofenac sodium 50 mg t.d.s. Since both indomethacin and diclofenac sodium are potent inhibitors of prostaglandin synthetase, these findings are consistent with the hypothesis tht prostaglandins are involved in the feed-back regulation of lipolysis, and mediate the inhibitory effect of lipolysis on lipoprotein lipase activity.

Serum lipoproteins in diabetes: relation of alpha-lipoprotein level to therapy.

Three hundred and sixty diabetic patients (125 on insulin, 109 on sulfonylureas and 126 on diet alone) were selected to investigate the effect of the type of treatment and of the degree of metabolic control on serum lipoproteins. Prebeta-lipoprotein concentration was higher than normal in all treatment groups. Beta-lipoproteins were significantly higher in diabetic women than in controls. No difference in beta- and prebeta-lipoprotein concentration existed between the 3 treatment groups. Alpha-lipoproteins were significantly higher in insulin-treated than in diet-treated patients irrespective of the degree of metabolic control. The daily dose of insulin and, in patients on diet or sulfonylureas, serum IRI were positively correlated to alpha-lipoprotein concentration while this lipoprotein fraction was not significantly correlated to fasting blood sugar. Alpha-lipoprotein concentration, then, appears to be markedly influenced by exogenous and endogenous insulin, independently of the degree of metabolic control.

Dopaminergic control of serum potassium.

Metoclopramide, a dopaminergic inhibitor, injected in 9 normal volunteers, was followed by a prompt decrease of serum potassium (10--20 min; p less than 0.01) and by an increase of plasma aldosterone (p less than 0.01). Renin slightly increased at 45 min (p less than 0.05); insulin and cortisol did not show any significant increase. The urinary excretion of potassium rose after metoclopramide (p less than 0.05). A bolus of aldosterone (250 micrograms i.v.) in 4 normal subjects was not followed by any modification of serum potassium, but increased urinary potassium excretion (p less than 0.05); the injection of metoclopramide in two patients with an aldosterone-secreting adenoma of the adrenal and in one patient with Addison's disease induced a decrease of serum potassium in absence of any modification of plasma aldosterone. The decrease of serum potassium after metoclopramide is not explained by changes of aldosterone or insulin, considered the most important hormonal controls of potassium. The rapidity of potassium decrease implies a change of distribution of potassium between extra- and intracellular compartments, which, in turn, may stimulate aldosterone secretion. It is conceivable that the dopaminergic system has a role in the control of serum potassium.

Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects.

Normal subjects and patients with adult-onset diabetes received 10 gm. of aspirin in four days. On the fourth day, the fasting serum glucose and the glucose response to oral glucose were decreased in both groups. These changes were associated with increased levels of serum insulin and pancreatic glucagon, although the glucagon responses to oral glucose were unchanged. In the diabetic patients, aspirin therapy was followed by a decreased glucose response to I.V. glucose and by the appearance of an early insulin peak, which could not be demonstrated before treatment. Aspirin did not affect the I.V. glucose tolerance in normal subjects, although it did enhance the early insulin peak. A decrease in the fasting levels of free fatty acids was noted in both groups, whereas the fasting level of triglycerides decreased only in the diabetic patients. Cholesterolemia did not change in either group. A few preliminary observations indicate that, in normal subjects, ibuprofen and ketoprofen, two other presumed prostaglandin inhibitors, did not affect fasting glycemia, glucose tolerance, or the insulin response to glucose. No changes were noted after the administration of placebo.

Metoclopramide increases plasma aldosterone concentration in man.

Plasma Aldosterone (PA) response to metoclopramide (10 mg i.v.) was studied in 11 normal, 2 hypophysectomized subjects and in one patient with bilateral adrenal hyperplasia. All the subjects were kept on a normal sodium and potassium intake. Four normal subjects were pretreated with 1 mg of dexamethasone in order to inhibit endogenous ACTH. In all subjects metoclopramide elicited a prompt rise of PA comparable to that obtained with angiotensions or ACTH. No significant change of blood pressure, serum electrolytes, plasma renin activity, Plasma Cortisol (PC) was detected. The lack of PC response to metoclopramide and the PA increase in dexamethasone pretreated subjects rule out an ACTH mediated effect. The increase of PA in hypophysectomized subjects, in whom metoclopramide did not stimulate any prolactin release, rules out a prolactin mediated effect. Metoclopramide increases plasma aldosterone concentration probably via a direct action on the adrenal glomerular zone or throught another unknown mechanism.

Effects of acetylsalicylic acid and indomethacin on growth hormone secretion in man.

To investigate the possibility that prostaglandins (PG) take part in the control of growth hormone (GH) secretion in humans, we have studied the effects of protracted and acute administration of acetylsalicylic acid (ASA) and indomethacin (ID), two PG synthesis inhibitors, on basal and insulin-stimulated GH secretion in normal volunteers. In eight subjects, oral administration of 3-2 g daily of ASA for 4 days clearly reached GH response to insulin hypoglycemia (p less than 0.01, ANOVA). In six additional subjects, GH response to hypoglycemia was not modified by a 4-day oral treatment with 300 mg daily of ID. The pattern of plasma free fatty acids (FFA) and blood glucose during the insulin tolerance test was not significantly affected by ASA treatment. After ID the O time value of the above parameters was somewhat higher than under basal conditions, while the drop of blood glucose, but not to FFA, was slightly more pronounced. Acute oral administration of 1.5 g ASA in 12 subjects did not appreciably modify baseline plasma GH, FFA, and blood glucose levels. By contrast, a single oral dose of 100 mg ID in 12 subjects caused a moderate but significant rise (p less than 0.05) of plasma GH levels together with a clear elevation (p less than 0.01) of plasma FFA and blood glucose levels with respect to a group of controls treated with a placebo. Collectively these results are compatible with the possibility that PG play a physiologic stimulating role in the control of GH secretion, although an effect of ASA and ID unrelated to PG inhibition cannot be ruled out, In any event, in view of the number of endocrine and metabolic alterations induced by ASA and ID, these drugs seem to merit further study.