Timothy S. Harrison

β-2-adrenergic stimulation of ornithine decarboxylase activity in porcine granulosa cells in vitro

Abstract Epinephrine, norepinephrine, and isoproterenol produced dose-dependent stimulation of ornithine decarboxylase (EC 4.1.1.7) activity in isolated porcine granulosa cells maintained under defined conditions in vitro. β- but not α-receptor-blocking agents prevented enzyme stimulation by catecholamines. Application of preferential β-1 and β-2-receptor antagonists and agonists localized the epinephrine effect to β-2-adrenergic mediation. Epinephrine action was enhanced by the phosphodiesterase inhibitor, 1-methyl-3-isobutyl-xanthine, but not by saturating concentrations of the cyclic AMP analogue, 8-bromocyclic AMP, of follicle-stimulating hormone, or of prostaglandin E 2 . However, stimulation by epinephrine was additive to that of luteinizing hormone. Follicular fluid obtained from immature Graafian follicles contined concentrations of norepinephrine and epinephrine active in vitro. Thus, catecholamines may participate in the regulation of ornithine decarboxylase activity in the ovary. Catecholamine effects may be mediated by β-2-receptors linked to the adenylate cyclase system.

Prevalence of diffuse pancreatic beta islet cell disease with hyperinsulinism: Problems in recognition and management

Among 77 patients with endogenous hyperinsulinism seen in 2 medical centers, diffuse islet cell disease accounted for 17 (22%) patients. Since diffuse islet cell disease poses special problems in management, its prevalence is emphasized in this report.Among these patients with diffuse islet cell disease, there were 11 patients with adenomatosis, 4 with nesidioblastosis, and 2 with islet cell hyperplasia. Six of the 77 patients were found in multiple endocrine neoplasia, type I kindreds; diffuse islet cell disease was documented in 4 of these patients.We outline principles of management in patients with diffuse islet cell disease. Frozen section microscopy failed to identify nesidioblastosis or islet cell hyperplasia.RésuméChez 77 malades, provenant de 2 centres médicaux, qui présentaient un hyperinsulinisme endogène, 17 cas de lésions diffuses des îlots de Langerhans ont été dénombrés. Ce fait est donc loin dêtre exceptionnel et cette étude a pour but de le souligner.Parmi ces 17 malades, 11 présentaient des adénomes multiples (adénomatoses), 4 des nésidoblastomes (anomalies tissulaires multifocales), 2 des hyperplasies cellulaires insulaires. Chez ces 77 malades, 6 cas de MEN type I furent individualisés, 4 dentre eux présentaient une maladie insulaire diffuse.Les auteurs, forts de cette expériences insistent sur les principes du traitement de ce type daffection. Ils insistent sur le fait que létude histologique extemporanée ne permet pas didentifier les nésidoblastomes et les hyperplasies cellulaires insulaires et que dans 70%–80% des cas les résections pancréatiques ne permettent pas dobtenir la guérison.ResumenUn problema constante para el cirujano que opera pacientes con hiperinsulinismo endógeno es el de qué hacer cuando no se encuentre patología en el curso de la operación una vez realizada la exploración preliminar del páncreas. Los adenomas solitarios de células beta pueden pasar desapercibidos cuando no son palpables; la identificación de la enfermedad difusa de las células insulares plantea muchos problemas. Reconocemos tres alteraciones principales de tipo difuso: adenomatosis de células beta, nesidioblastosis e hiperplasia pancreática de células beta. Además, múltiples macroadenomas pueden coexistir o no con microadenomatosis o con hiperplasia en ciertos pacientes con hiperinsulinismo. Los desórdenes de células insulares de tipo multifocal son particularmente frecuentes en pacientes con Neoplasia Endocrina Multiple Tipo I.Entre 77 pacientes con hiperinsulinismo endógeno observados en dos centros médicos, la enfermedad de células insulares de tipo difuso estuvo presente en 17 pacientes (22%). Teniendo en cuenta que la enfermedad de células insulares de tipo difuso plantea problemas especiale s en cuanto a su manejo, este informe hace énfasis en lo relativo a su prevalencia.En el grupo de pacientes con enfermedad de células insulares de tipo difuso se encontraron 11 pacientes con adenomatosis, cuatro con nesidioblastosis y dos con hiperplasia de células insulares. Seis de los 77 pacientes fueron hallados en familiares con Neoplasia Endocrina Multiple Tipo I; la enfermedad difusa de células insulares fue documentada en cuatro.Se presentan los principios de manejo en pacientes con enfermedad de células insulares de tipo difuso. La miscroscopía de cortes por congelación falló en la identificación de la nesidioblastosis o la hiperplasia de células insulares.

Malignant catecholamine-secreting carotid body paraganglioma.

The second known case of a malignant catecholamine-secreting (DA)-secreting carotid body paraganglioma is presented. Dopamine synthesis and secretion can be increased in malignant tumors derived from neural crest cells. Whether this is true, in addition, for extra-adrenal paragangliomas is not yet clear. Malignant paragangliomas of the carotid body and larynx, although rare, frequently have been accompanied by increased catecholamine secretion. Malignant catecholamine-secreting carotid body paragangliomas are best treated by composite resection (internal carotid artery and neck dissection), with special attention being given to measures preventing severe hypertension and arrhythmias in the perioperative period.

HPLC for urinary catecholamines and metanephrines with alpha-methyldopa

In five healthy selected volunteers with normal blood pressure and one pheochromocytoma patient, high performance liquid chromatography (HPLC) has been evaluated, with electrochemical detection for quantitation of urinary catecholamines and metanephrines during administration of the antihypertensive, alpha-methyldopa. The clinical usefulness of HPLC is compared with that of the conventional assay method--the trihydroxyindole (THI)-fluorometric procedure. The THI fluorometric method is known to suffer from true false-positive interference as a result of its inability to differentiate between alpha-methyldopa, its primary metabolic derivatives, and the structurally similar endogenous catecholamines. It is shown that the HPLC separation methodology yields accurate, reproducible results devoid of interference from the presence of alpha-methyldopa. Free urinary excretion rates of epinephrine, norepinephrine, and dopamine were elevated by alpha-methyldopa, P less than 0.001, for epinephrine, norepinephrine, and dopamine when measured by the trihydroxyindole technique but not with high performance liquid chromatography. With alpha-methyldopa treatment, urinary normetanephrine excretion rates were slightly increased, P less than 0.05, by fluorometric analysis and slightly decreased. P less than 0.05, when measured by HPLC. Of added interest, the formation of the normetanephrine analog of alpha-methyldopa, previously undetected, is suggested. Slightly elevated metanephrine levels are seen by the THI-fluorometric method in the presence of alpha-methyl metanephrines. Establishing that the HPLC assay procedure is suitable for clinical diagnosis of pheochromocytoma, despite the presence of alpha-methyldopa, makes it unnecessary to discontinue use of this antihypertensive in screening for pheochromocytoma.

Converting enzyme inhibition with captopril in patients with primary hyperaldosteronism

The humoral and hemodynamic effects of converting enzyme inhibition with captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (±SEM) plasma renin activity (PRA) rose from 5.0 ± 1.4 to 35.3 ± 5.3 ng/ml/hr (P < 0.001) and mean (±SEM) plasma aldosterone (PA) declined from 25.8 ± 2.9 to 15.1 ± 1.9 ng/ml (P < 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone‐producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive.

Site-dependent central effects of aldosterone in rats

A relationship between the subcommissural organ (SCO) and the adrenal glands has long been suspected. This report provides further information about the effects of a continuous D-aldosterone infusion into the SCO area of conscious, adult male Sprague-Dawley rats. A 6-day aldosterone infusion (5 ng/h) increased urinary sodium excretion, decreased adrenal medullary cross-sectional area, elevated adrenal corticosterone content and terminal plasma epinephrine concentration. Mineralocorticoid infusions directly into a lateral cerebral ventricle did not affect these parameters but, unlike SCO area infusions, decreased consummatory behavior. Infusions of tritiated aldosterone into the SCO area revealed that radioactivity was mainly confined to dorsomedial portions of the brain near the SCO, whereas the pineal body contained only background radioactivity. The data support the concept that the SCO area interacts with physiological systems related to both the adrenal cortex and medulla.

Renal modulation of electrically stimulated adrenal medullary secretion

In acutely anephric dogs, depressed reflex adrenal medullary secretion (AMS) may be related to low plasma angiotensin. Either local (adrenal medulla) or central nervous system mechanisms are responsible. Local influences of acute bilateral nephrectomy on AMS were evaluated after left splanchnic nerve section. Two groups of five healthy, fasted mongrel dogs (16-20 kg) were prepared (Na pentobarbital iv anesthesia, 98% O2/2% CO2, Harvard volume ventilator) at celiotomy with blood pressure and sampling catheters per femoral arteriotomies and left adrenal-femoral venous T-shaped Silastic shunt. Group 2 dogs had acute bilateral nephrectomy. The acutely divided distal left splanchnic nerve was arranged for electrical stimulation (Grass, bipolar nerve stimulator, 1 0 V, 1-msec delay, 10 Hz, 10-msec square wave). Heparin anticoagulation was maintained and arterial pH monitored. Simultaneous adrenal vein, aortic blood sampling, and adrenal blood flow (F) determinations followed 10-min periods of alternating electrical stimulation and nerve rest. AMS for epinephrine (E) and norepinephrine (NE) was calculated [E and NE plasma concentration (single isotope radioenzymatic technique) differences of adrenal vein minus aorta multiplied by F]. Results were grouped, analyzed for variance, and compared (Wilcoxon unpaired rank sum, Students test, Fischers tables, ANOVA). Low aortic E, NE concentrations confirmed absent systemic adrenergic stimulation. The AMS ratio of NE:E was low in the anephric group. At the first stimulation interval NE:E was 0.28 +/- 0.14 (1 SD) in renal intact dogs vs 0.11 +/- 0.04 in anephric dogs, P less than 0.05. At rest NE:E was 0.33 +/- 0.12 in group 1 vs 0.17 +/- 0.02 in group 2 dogs, P less than 0.02. Plasma NE was also low in the anephric group (289 mg/liter +/- 126 (1 SD) vs 612 +/- 189, P = 0.033, resting).(ABSTRACT TRUNCATED AT 250 WORDS)