Lawrence M. Fishman

Heparin-Induced Aldosterone Suppression and Hyperkalemia

PURPOSE To review the effects of heparin and heparinoid compounds on aldosterone physiology and associated induction of hyperkalemia. MATERIALS AND METHODS A comprehensive literature search (of human and animal data) was carried out by computer and by using reference citations from primary sources. RESULTS Heparin and its congeners are predictable, potent inhibitors of aldosterone production. This inhibitory effect is specific for the zona glomerulosa; other corticosteroids are not affected. Aldosterone suppression occurs within a few days of initiation of therapy, is reversible, and is independent of either anticoagulant effect or route of administration. Decreases in aldosterone levels may occur with heparin dosages as low as 5,000 U BID. The most important, but probably not the only mechanism of aldosterone inhibition appears to involve reduction in both the number and affinity of the angiotensin-II receptors in the zona glomerulosa. Prolonged use of heparin causes marked reduction in the width of the adrenal zona glomerulosa. CONCLUSIONS Aldosterone suppression results in natriuresis and less predictably in decreased excretion of potassium. Greater than normal serum potassium levels occur in about 7% of patients, but marked hyperkalemia generally requires the presence of additional factors perturbing potassium balance (in particular, renal insufficiency, diabetes mellitus, or the use of certain medications). Heparin-induced increases in serum potassium need to be better anticipated by clinicians. Serum potassium levels should be monitored periodically in patients being given heparin for 3 or more days, and in patients at relatively high risk for hyperkalemia, the monitoring interval should probably be no greater than 4 days.

Pheochromocytoma. Lateral versus anterior operative approach.

The possibility of bilateral, extra-adrenal, and malignant tumors has dictated a thorough abdominal exploration through an anterior incision in the management of patients with pheochromocytomas. Careful visualization or palpation of the sites known to harbor secondary tumors is still recommended by many surgeons. The present study contrasts the results and morbidity of the retroperitoneal approach with that of the intraperitoneal operative approach for resection of pheochromocytoma. In the last 14 years, 37 patients had successful total resections of their pheochromocytomas, excluding one patient with metastasis to the liver at the time of surgery who died 10 years after operation. After preoperative localization of their tumors, 17 patients were explored anteriorly and 20 underwent resection using a lateral approach. Thirty-one patients have been followed from 2 to 141 (average 56) months. All patients have either returned to a normotensive state on no medication (27 patients) or, while requiring medication (9 patients), have had normal urinary metanephrine/catecholamine levels, except for the one patient with metatastic disease. There were substantial differences in morbidity rates between the two groups, however. Four patients (20%) had minor postoperative complications, following retroperitoneal resection that included pleural effusion, urinary retention, pulmonary congestion, and fever. Nine patients (53%) had complications when the anterior approach was used, including splenectomy in two, pneumonia, and postoperative fever. Postoperative hospital stay averaged 9.8 days (range, 4 to 21 days) for the anterior group and 6.1 days (range, 4 to 12 days) when a lateral approach was used (p = 0.002). Our data suggest that, with accurate unilateral localization, the flank, retroperitoneal approach for resection of pheochromocytoma can be used successfully with less morbidity.

Review of the Literature: Severe Hyperphosphatemia

A patient with a markedly elevated serum phosphorus level (23.9 mg/dL) is described, followed by a brief review of severe hyperphosphatemia. Elevated serum phosphorus levels may be artifactual or true. True hyperphosphatemia is usefully subdivided according to (a) whether phosphorus is added to the extracellular fluid from a variety of exogenous or endogenous sources, or (b) whether the urinary excretion of phosphorus is reduced from either decreased glomerular filtration or increased tubular reabsorption. Severe hyperphosphatemia, defined herein as levels of 14 mg/dL or higher, is almost invariably multifactorial--usually resulting from addition of phosphorus to the extracellular fluid together with decreased phosphorus excretion. The hyperphosphatemia of the patient described herein appeared to result from a combination of dietary phosphorus supplementation, acute renal failure, acute pancreatitis, and ischemic bowel disease, complicated by lactic acidosis.

Effects of marine sponge extracts on mitogen-activated protein kinase (MAPK/ERK1,2) activity in SW-13 human adrenal carcinoma cells

Some species of marine sponge have been shown to produce metabolites with endocrine-altering and cell growth regulatory properties. Since cell division and differentiation are controlled, in part, by the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK/ERK) cascade, we tested extracts (1.0mg/ml) from six shallow water marine species obtained in the Florida Keys for effects on MAPK/ERK(l,2) (sub-variant of EC 2.7.1.37) activity in incubations with SW-13 human adrenal carcinoma cells in culture. In these short-term incubations, extracts from two species, the purple bleeding sponge (Iotrochota birotulata) and the West Indian bath sponge (Spongia barbara), significantly inhibited MAPK/ERK(1,2) activity (to 51 and 44% of control levels, respectively) without altering cell survival. Western blots for phosphorylated and total ERK showed that ERK(2) predominated over ERK(1) by a factor of about 4:1 and that the phosphorylated forms of these isozymes were strongly suppressed by active extracts from both sponges. Another species, the green sponge (Haliclona veridis), whose extract has been shown previously to activate guanylate cyclase and to inhibit adenylate cyclase in a variety of mammalian tissues, was found not to affect MAPK/ERK(1,2) in human adrenal carcinoma cultures but did lyse and kill most of these cultured cells. Extracts from the sheepswool sponge (Hippospongia lachne) and the bleeding sponge (Oligoceras hemorrhages) did not significantly affect either MAPK/ERK(1,2) activity or the survival of attached cells. An extract from the fire sponge (Tedania ignis) did not alter MAPK/ERK(1,2) activity but did modestly decrease cell viability. These studies document for the first time species-specifc effects of marine sponge extracts on the MAPK/ERK(1,2) cascade and on the growth and survival of human adrenal carcinoma cells in culture.

Effects of aminoglutethimide, metyrapone, and ascorbic acid on testicular metabolism of cholesterol

The effects of aminoglutethimide (AG), metyrapone (MET), and ascorbic acid (AA) on the conversion of labeled cholesterol to testosterone (T) by the mature rat testis were examined and compared under identical in vitro conditions. In cell-free testicular homogenates, formation of labeled T from cholesterol-4-14C was depressed in a dose-related manner by AG and MET in concentrations ranging from 0.03 to 1.0 mM; AG was the more potent inhibitor at each concentration tested. Within this range of concentrations, AA induced a slight stimulation of the conversion of cholesterol-4-14C to T, with inhibition demonstrable only above 5.0 mM. Halfmaximal inhibition of T formation was attained with 0.1, 0.3, and 6.4 mM concentrations of AG, MET, and AA, respectively. When the synthesis of T was almost completely prevented by any of these agents, no accumulation of known intermediates between cholesterol and T could be demonstrated. Under these conditions, MET had no effect on the conversion of pregnenolone-4-14C to T or several T precursors or on the rate of metabolic degradation of testosterone-4-14C. Since the generation of the six-carbon fragment resulting from side chain cleavage of cholesterol-26-14C by rat testicular mitochondrial suspensions was also inhibited by AG, MET, and AA, the depression of steroid production affected by these agents in the testis appears to be related to their capacity to block the reaction cholesterol pregnenolone, as previously demonstrated in the adrenal and ovary. AG, MET, and AA thus inhibit cholesterol cleavage in adrenal and gonadal tissues as well as 11β-hydroxylation in the adrenal. In view of the similarities between the enzyme systems affected, it is likely that AG, MET, and AA exert their inhibitory effects on steroid-forming tissues through similar mechanisms.

Thyrotoxic periodic paralysis in a Black male

The findings and course in a 55-year-old Black man with thyrotoxic periodic paralysis are described. This disorder appears to have a strong predilection for Orientals (∼ 90% of reported cases) with occasional reports in Caucasians and only one previous description in a Black. HLA phenotyping of the reported patient demonstrated neither of the two genetic markers previously noted among Chinese with thyrotoxic periodic paralysis, indicating that these haplotypes do not serve as markers for the disorder in Blacks.

Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture.

Adrenocortical carcinoma is an uncommon malignancy that is usually fatal within a short time after diagnosis. We have investigated the effects on the growth and survival of SW-13 human adrenal carcinoma cells in culture of some currently used and some potentially new agents in the treatment of adrenal cancer. Established drugs tested were mitotane, cisplatin, etoposide, 5-fluorouracil, and suramin. Other agents studied included adenine arabinofuranoside, cytosine arabinofuranoside, 2-methoxyestradiol, and paclitaxel. The most potent chemotherapeutic agents in this system were paclitaxel and 2-methoxyestradiol, with EC (50) of 1.8x10 (-8) and 3.3x10 (-7) M, respectively. Cytosine arabinofuranoside and cisplatin both had the same EC (50) of 7.0x10 (-7) M, and etoposide 1.1x10 (-6) M. All the other agents tested required much higher doses for effect, including mitotane, the current most commonly used chemotherapy for adrenal cancer, with an EC (50) of 3.3x10 (-4) M. These data suggest that paclitaxel, 2-methoxyestradiol, and cytosine arabinofuranoside should be further evaluated for their potential in the chemotherapy of adrenal carcinoma.

Influence of Ethanol on Fetal Brain Cholinergic Enzyme Activities

Cultured brain cells from rat fetuses of ethanol-treated mothers demonstrated more than 2-fold elevations in choline acetyltransferase (ChAT) activity relative to those of control (saline-exposed) fetal brain cells. When cells from control animals were incubated in vitro for 5 days with 0.1% ethanol, ChAT activity was found to increase more than 4-fold. Brain cells from in utero ethanol-treated animals further exposed to ethanol in vitro for 5 days demonstrated significantly higher ChAT activity compared to cells exposed to ethanol only in vivo. These levels were more than 6 times greater than those of central nervous system cells never exposed to ethanol. Acetylcholinesterase (AChE) activity was significantly elevated (greater than 4-fold) in fetal brain cells when ethanol was present both in vivo and in vitro, but neither treatment alone resulted in any significant changes in AChE. These effects of ethanol on enzymes involved in acetylcholine metabolism may contribute to the different developmental neurologic abnormalities associated with fetal alcohol exposure.

Corticosteroid effects on cholinergic enzymes in ethanol-treated fetal brain cell cultures

In the presence of ethanol, corticosterone and dexamethasone inhibit choline acetyltransferase and acetylcholinesterase activities in cultured fetal brain cells of the rat. These results suggest that corticosteroids may have an important influence on the activity of cholinergic enzymes in the fetal brain and may antagonize the effects of ethanol in this setting.

Biosynthesis of androgens by pheochromocytomas

Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone. In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield. The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex. Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors. In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate [4-14C] cholesterol into either androgens or corticosteroids. The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.