Adverse medical complications: an under-reported contributory cause of death in New York City.

OBJECTIVES: The current death certification system in the USA fails to accurately track deaths due to adverse medical events. The aim of this study was to demonstrate the under-reporting of deaths due to adverse medical events due to limitations in the current death certification/reporting system, and the benefits of using the term 'therapeutic complication' as the manner of death. STUDY DESIGN: Retrospective review and comparison of death certificates and vital statistical coding. METHODS: The manner of death is certified as a therapeutic complication when death is caused by predictable complications of appropriate therapy, and would not have occurred but for the medical intervention. Based on medical examiner records, complications that caused or contributed to deaths over a five-year period were examined retrospectively. These fatalities were compared with deaths coded as medical and surgical complications by the New York City Bureau of Vital Statistics. RESULTS: The Medical Examiner's Office certified 2471 deaths as therapeutic complications and 312 deaths as accidents occurring in healthcare facilities. In contrast, the New York City Bureau of Vital Statistics reported 188 deaths due to complications of medical and surgical care. CONCLUSIONS: Use of the term 'therapeutic complication' as the manner of death identified nearly 14 times more deaths than were reported by the New York City Bureau of Vital Statistics. If these therapeutic complications and medical accidents were considered as a 'disease', they would rank as the 10th leading cause of death in New York City, surpassing homicides and suicides in some years. Nationwide policy shifts that use the term 'therapeutic complication' would improve the capture and reporting of these deaths, thus allowing better identification of fatal adverse medical events in order to focus on and assess preventative strategies.

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Management and outcome of the dislocated hip hemiarthroplasty.

AIMS: This study describes and compares the operative management and outcomes in a consecutive case series of patients with dislocated hemiarthroplasties of the hip, and compares outcomes with those of patients not sustaining a dislocation. PATIENTS AND METHODS: Of 3326 consecutive patients treated with hemiarthroplasty for fractured neck of femur, 46 (1.4%) sustained dislocations. Of the 46 dislocations, there were 37 female patients (80.4%) and nine male patients (19.6%) with a mean age of 83.8 years (66 to 100). Operative intervention for each, and subsequent dislocations, were recorded. The following outcome measures were recorded: dislocation; mortality up to one-year post-injury; additional surgery; residential status; mobility; and pain score at one year. RESULTS: Of 43 dislocations, 30 (70%) occurred within one month and 42 (98%) occurred within three months of hip fracture surgery. Seven (16%) of these patients were treated with a single closed reduction and sustained no further dislocations. Four (9%) were treated with open reduction and experienced no further dislocations. Three (7%) hips were left dislocated and the remaining 32 (74%) patients required additional surgery of further closed reduction, revision, or excision arthroplasty. The one-year mortality rates for patients treated with two or fewer reductions (open or closed), successful revision arthroplasty, and excision arthroplasty were 3/14 (21%), 1/7 (14%), and 8/14 (57%) respectively. The only statistically significant difference in mortality was the difference between patients who did not sustain a dislocation and those who did and were treated by excision arthroplasty (p = 0.03). Patients treated by excision arthroplasty had the greatest reduction in mobility scores and highest pain scores. The excision arthroplasty group also included the greatest proportion of patients not able to mobilize and the smallest proportion of patients remaining in their own home. CONCLUSION: Most dislocations of hemiarthroplasties of the hip occur within one month of surgery. Closed reduction is generally unsuccessful. For those patients with unsuccessful closed reduction, revision arthroplasty should be considered when possible, as this results in a better functional outcome with a lower mortality than excision arthroplasty.

Beta endorphin selectively stimulates aldosterone secretion in hypophysectomized, nephrectomized dogs.

We examined the effects of synthetic human beta-endorphin (beta END) and a stable methionine (Met)-enkephalin analogue on aldosterone and cortisol secretion rates in anesthetized, hypophysectomized, and nephrectomized dogs and compared them to those of (1-39) ACTH. The circulation of the adrenal glands was completely isolated on the arterial and venous sides (Hilton Pouch). The peptides were infused to deliver 3 pmol/min into the aortic "pouch." Blood was collected from the vena caval pouch, which received blood only from the adrenal gland. Secretion rates of aldosterone and cortisol were calculated as the product of adrenal blood flow and venous steroid concentration. Duplicate steroid measurements were obtained during a control period, at 10, 30, and 50 min of peptide infusion and during a postcontrol period. BetaEND increased aldosterone secretion rate from 2.4 +/- 0.5 ng/min (mean +/- SEM) to 3.2 +/- 0.9 ng/ min at 10 min (N.S.), 8.2 +/- 2.5 ng/min (P less than 0.05) at 30 min and 11.0 +/- 3.7 ng/ min (P less than 0.05) at 50 min of infusion. Cortisol secretion rate was not affected by infusion of betaEND. Infusion of the stable Met-enkephalin analogue D-alanine2; Metphenylalanine4, Met(O)-enkephalin-ol or saline alone had no effect on aldosterone or cortisol secretion rates. ACTH infusion increased mean aldosterone secretion rate by approximately 215% and significantly stimulated cortisol secretion rate. These results indicate that beta END selectively stimulates aldosterone secretion with a potency similar to that of an equimolar dose of ACTH.

Role of the sympathetic nervous system in the renal response to hemorrhage.

In 12 studies, a femoral artery and vein of a donor dog treated with desoxycorticosterone were connected by tubing to a renal artery and vein of a recipient dog treated with desoxycorticosterone, and the kidney with its nerve supply intact was perfused at femoral arterial pressure. Infusion of normal saline, which contained albumin, from 2.7 to 3.1 g/100 ml, in the donor produced significant natriuresis in a kidney of the donor (from 112 to 532 muEq/min) and in the perfused kidney (from 60 to 301 muEq/min) of the recipient. Increased sodium excretion in the perfused kidney was associated with an increase in the clearances of inulin and para-aminohippurate (P < 0.01) and a decrease in hematocrit of perfusing blood (P < 0.01). Infusion was continued in the donor while recipient was bled 23 ml/kg, with a decrease in mean arterial pressure from 152 to 130 mm Hg. Sodium excretion in perfused kidney decreased from 301 to 142 muEq/min (P < 0.01), whereas sodium excretion in donor was unchanged (506 VS. 532 muEq/min; P > 0.3). Clearance of inulin by perfused kidney was not significantly affected by bleeding (26 +/-SE 2 VS. 25 +/-SE 2; P > 0.2), but the clearance of para-aminohippurate was decreased by bleeding (P < 0.01), so that filtration fraction increased. As the perfused kidney of the recipient dog continued to receive blood from the natriuretic donor dog when the recipient dog was bled, the decrease in sodium excretion that bleeding produced in the perfused kidney was presumably mediated by renal nerves. Thus, an increase in nervous stimuli to the kidney that is not sufficient to decrease glomerular filtration rate can increase the tubular reabsorption of sodium and thereby significantly decrease its excretion. This property of the sympathetic nervous system to affect tubular reabsorption of sodium suggests that an increase in sympathetic activity may constitute an important mechanism for the renal conservation of sodium when intravascular volume is contracted by hemorrhage or other cause.

Depression of proximal tubular sodium reabsorption in the dog in response to renal beta adrenergic stimulation by isoproterenol.

Water diuresis was produced in anesthetized hypophysectomized, cortisone-treated dogs by infusion of 2.5% dextrose. Alpha adrenergic blockade of the left kidney produced by infusion of phenoxybenzamine in the left renal artery was associated with a significantly (P < 0.05) greater rate of urine flow (V) and free water excretion (C(H2O)) in the left kidney than in the right despite similar glomerular filtration rates (GFR) (17 +/- 1.3 ml/min, left; 18 +/-0.9 ml/min, right). Sodium excretion (U(Na)V) was similar in the two kidneys (3 and 5 muEq/min). When beta adrenergic stimulation of the left kidney was superimposed on alpha blockade by the addition of isoproterenol to the left renal artery infusate, GFR remained unchanged and similar in the two kidneys, as V and C(H2O) increased significantly (P < 0.01) in the left kidney but not in the right. When isoproterenol was discontinued, V and C(H2O) returned towards control in the left kidney and remained unchanged in the right. The ratios of the left kidney to the right during control, isoproterenol, and postcontrol were 1.22, 1.65, and 1.35, respectively, for V and 1.36, 1.90, and 1.44, respectively, for C(H2O). Sodium excretion remained unchanged and similar in the two kidneys throughout the study. The results indicate that blockade of alpha adrenergic activity inhibits the increased proximal tubular sodium reabsorption which anesthesia induces in the dog. Beta adrenergic stimulation appears to decrease proximal tubular sodium reabsorption but does not prevent virtually complete reabsorption of the increased quantity of delivered sodium by the ascending limb of the loop of Henle and the distal tubule. These changes in sodium reabsorption presumably are not associated with changes in colloid osmotic pressure or hydrostatic pressure in the peritubular capillary inasmuch as cortical and non-cortical plasma flow, filtration fraction, and mean arterial pressure in the left kidney were unchanged. Thus, isoproterenol probably produced its effects through a direct action on the renal tubule, possibly through the mediation of the adenyl cyclase system.

Renal effects of adenosine 3',5'-cyclic monophosphate and dibutyryl adenosine 3',5'-cyclic monophosphate. Evidence for a role for adenosine 3',5'-cyclic monophosphate in the regulation of proximal tubular sodium reabsorption.

Stable water diuresis was produced in anesthetized, hydrocortisone-treated hypophysectomized dogs by infusion of 2.5% dextrose. Infusion of adenosine 3',5'-cyclic monophosphate (cyclic AMP) in the left renal artery decreased ipsilaterally glomerular filtration rate (GFR), cortical and non-cortical renal plasma flow, and tended to increase urine flow (V) and free-water clearance (C(H2O)) despite a decrease in mean arterial pressure. Infusion of dibutyryl adenosine 3',5'-cyclic monophosphate (dibutyryl cyclic AMP) in the left renal artery increased V and C(H2O) significantly (P<0.01) bilaterally with essentially no change in GFR, in total renal plasma flow or its cortical and non-cortical components. For each kidney the magnitude of the change in V was similar to the magnitude of the change in C(H2O) and the change in sodium excretion was trivial. Cyclic AMP probably produced its effects on renal hemodynamics and mean arterial pressure wholly or in part through the action of metabolites such as 5'-AMP and adenosine on the renal and systemic vasculature. The absence of an effect of dibutyryl cyclic AMP on renal hemodynamics and its bilateral effect may be explained by the resistance of this nucleotide derivative to metabolism. Dibutyryl cyclic AMP appears to decrease by direct cellular effect(s) proximal tubular sodium reabsorption but does not prevent virtually complete reabsorption of the increased load of sodium in the distal nephron. This effect on the kidney is qualitatively and quantitatively similar to the effect of renal arterial infusion of isoproterenol. The results suggest that synthesis of cyclic AMP in proximal renal tubule cells in response to stimulation of beta adrenergic or other receptors can mediate a decrease in the proximal tubular reabsorption of sodium.

Correction of hypokalemia corrects the abnormalities in erythrocyte sodium transport in Bartter's syndrome.

In Bartter's syndrome, the defective renal tubular transport has been postulated to be a manifestation of a more generalized membrane abnormality. To explore this possibility, sodium concentration, ouabain-sensitive (pump transport), ouabain-resistant but furosemide-sensitive (Na-K-Cl cotransport), and ouabain- and furosemide-resistant (passive transport) 22Na effluxes were measured in erythrocytes obtained from nine patients with Bartter's syndrome before and during correction of hypokalemia. Intracellular [Na+] in erythrocytes obtained from nine patients with Bartter's syndrome was significantly (P less than 0.001) higher than that in 30 normal controls (11.8 +/- 1.8 vs. 7.3 +/- 1.4 mmol/liter cells). Pump transport and Na-K-Cl cotransport 22Na effluxes were significantly (P less than 0.01) increased, whereas the rate constant for these effluxes as well as for passive 22Na efflux did not differ from normal. Correction of hypokalemia and maintenance of a normal serum potassium decreased intracellular [Na+] to 8.2 +/- 1.8 mmol/liter cells, a normal value, and corrected the ouabain-sensitive and furosemide-sensitive 22Na effluxes. The results indicate that exposure of erythrocytes to a low potassium environment is responsible for the high intracellular [Na+] and, in turn, the high sodium efflux in Bartter's syndrome. The normal sodium efflux observed during correction of hypokalemia and the consistently normal rate constants for all three efflux parameters measured suggest that intrinsic sodium transport processes in erythrocytes are normal in Bartter's syndrome.

Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excretion and adrenergic activity in man.

The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136+/-18 (SE) and 37.4+/-5.3 mug/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195+/-20 mug/day (P<0.01) whereas urinary norepinephrine decreased to 21.1+/-3.0 mug/day (P<0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18+/-0.22 to 2.79+/-0.19 mug/20 min, P<0.01), but decreased plasma dopamine-beta-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and p-aminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait comprising hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium. We evaluated the role of parathyroid hormone in the relative hypocalciuria of FHH and characterized the renal transport of calcium in this disorder using three previously hypercalcemic FHH patients with surgical hypoparathyroidism and three controls with surgical hypoparathyroidism. Intravenous infusion of calcium chloride in two patients with FHH and in three controls increased serum calcium from a mean basal of 5.0 to a mean peak of 6.8 meq/liter in two FHH patients and from 4.2 to 5.7 in three control subjects. Urinary calcium in a third FHH patient was studied without calcium infusion during recovery from hypercalcemia of vitamin D intoxication. At all serum concentrations of calcium, calcium clearance was lower in FHH than in controls; at base-line serum calcium, the ratio of calcium clearance to inulin clearance (C(Ca)/C(IN)) in FHH subjects was 32% of that in controls and decreased to 19% during hypercalcemia. Calcium infusion increased the ratio of sodium clearance to inulin clearance in controls from a base line of 0.020 to 0.053 at peak concentrations of calcium in serum, but did not affect this parameter in FHH (0.017 at base-line serum calcium vs. 0.019 at peak). When calcium infusion studies were performed (in two patients with FHH and one control) during administration of acetazolamide, a drug whose principal renal action causes inhibition of proximal transport of solute, C(Ca)/C(IN) in the patients with FHH was 29 and 7% of that of the control at base-line and peak serum calcium, respectively. In contrast, ethacrynic acid, a diuretic that acts in the ascending limb of the loop of Henle, increased C(Ca)/C(IN) more in the FHH patients than in the control subject; C(Ca)/C(IN) was 65% at base-line and 47% at peak serum calcium, compared with that of the control subject. The greater calciuric response to ethacrynic acid than to acetazolamide or calcium infusion alone in FHH indicates that a major renal locus of abnormal calcium transport in this disorder may be the ascending limb of the loop of Henle.Decreased clearance of calcium in patients with FHH and hypoparathyroidism when compared with hypoparathyroid controls indicates that relative hypocalciuria in FHH is not dependent on hyperparathyroidism. Since the parathyroid glands in FHH are not appropriately suppressed by calcium, this implies that FHH represents a disorder of abnormal transport of, and/or response to, extracellular calcium in at least two organs, parathyroid gland and kidney.

Effect of aminoglutethimide on blood pressure and steroid secretion in patients with low renin essential hypertension.

An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117+/-2 (mean+/-SE) mm Hg to 108+/-3 mm Hg after 4 days of aminoglutethimide therapy and further to 99+/-3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6+/-7.2 kg in the control period to 80.6+/-7.0 kg after 4 days of drug treatment and to 80.1+/-6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16beta-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16beta-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62+/-0.5 (mean+/-SE) in the control period to 0.9+/-0.2 mug/24 h after 4 days and to 1.1+/-0.3 mug/24 h at the termination of aminoglutethimide treatment. The gradual lowering of blood pressure and body weight during aminoglutethimide therapy is consistent with the view that the antihypertensive effect of the drug is mediated through a reduction in the patients' extracellular fluid volume, probably secondary to the persistent decrease in aldosterone production. The observation that chronic administration of aminoglutethimide lowered blood pressure in these patients and elevated their plasma renin activity to the normal range without decreasing production of the adrenal steroids, deoxycorticosterone, 18-hydroxydeoxycorticosterone, and 16beta-hydroxydehydroepiandrosterone, makes it unlikely that these steroids are responsible either for the decreased renin or the elevated blood pressure in patients with low renin essential hypertension.

The kallikrein-kinin system in Bartter's syndrome and its response to prostaglandin synthetase inhibition.

The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

A sibship with hypokalemic alkalosis and renal proximal tubulopathy.

A new syndrome, characterized by hypokalemic alkalosis, hyperreninemia, aldosterone, high urinary prostaglandin E2 excretion, normal BP, and resistance of BP to angiotensin II is described in three of four siblings. Histologic examination of tissue obtained by biopsy from the kidneys showed an intense staining of the proximal tubular cells, as well as an extreme hypertrophy of the proximal tubular basement membranes, features that previously have not been observed. On electron microscopic examination, the characteristic changes of the tubular cells consisted of very dense cytoplasm, compact mitochondria, and pyknotic nuclei. In contrast to Bartter's syndrome, the juxtaglomerular apparatus were of normal appearance. Glomerular filtration rate and renal plasma flow were within normal limits. Fractional distal delivery of proximal tubular solute and fractional chloride reabsorption in the thick ascending limb of the loop of Henle were normal. The findings of a genetic linkage between the syndrome and the major histocompatibility system suggests that this familial tubulopathy is an inherited disorder.

Definitive use of external fixation for pelvic ring injuries (open book/APC2) in pregnancy.

Pelvic fractures in pregnancy are rare, resulting in a paucity of evidence-based management. We describe a case of open book pelvic injury in a 32-year-old woman in her third trimester of pregnancy. She was successfully managed with a supra-acetabular external fixator, which allowed the safe delivery of a healthy baby boy at 34 weeks, via caesarean section. The external fixator was removed postpartum, when the pelvis was deemed stable, and mother and baby both continue to do well. This is the only case in the literature that demonstrates the successful use of external fixation for pelvic injuries in pregnancy.

The role of prostaglandins in diabetes insipidus produced by desoxycorticosterone in the dog.

To determine the role of renal prostaglandins (PGs) in the renal response to desoxycorticosterone acetate (DOCA), dogs were studied on a constant diet in which sodium intake was restricted (2.5 meq/day) or high (115 meq/day). On the restricted sodium intake, DOCA (25 mg/day im for 6 days) did not affect urinary volume, sodium, potassium, PGE2, or PGF2 alpha. On the high sodium intake, DOCA produced sodium retention for 1 day and a sustained increase in urinary potassium with a fall in serum potassium to 3.1 meq/liter. Urine volume increased from 574 +/- 50 to 1726 +/- 177 ml/day (P less than 0.001) with a fall in urinary osmolality from 1545 +/- 122 to 495 +/- 55 mosmol/ liter (P less than 0.001) as serum sodium increased from 149.0 +/- 1.0 to 152.5 +/- 0.3 meq/liter (P less than 0.025) by the sixth day of DOCA. Urinary PGE2 and PGF2 alpha were unchanged during the first 2 days of DOCA, then increased progressively from control values of 261 +/- 60 and 1143 +/- 144 ng/day ng/day, respectively, to 730 +/- 62 (P less than 0.005) and 3013 +/- 479 ng/day (P less than 0.01), respectively. Potassium repletion during continued DOCA treatment restored urinary volume, osmolality, PGE2 and PGF2 alpha, and serum sodium to control values. Treatment with indomethacin during DOCA-induced hypokalemia, polyuria, hypernatremia, and increased urinary PG, restored urinary PGs to control values, and corrected the polyuria and hypernatremia without a change in serum potassium. Thus, DOCA produced potassium depletion, polyuria, increased urinary PGs, and hypernatremia in dogs on a high sodium intake but not in those on a restricted sodium intake. As polyuria and hypernatremia were corrected either by potassium repletion, which corrected the supranormal renal synthesis of PGs, or by indomethacin, which inhibited their synthesis, renal water loss was presumably the result of an increase in renal PG synthesis, probably stimulated by potassium depletion.

Overproduction of sodium-retaining steroids by the zona glomerulosa is adrenocorticotropin-dependent and mediates hypertension in dexamethasone-suppressible aldosteronism.

Dexamethasone suppressed urinary aldosterone to less than 1.5 micrograms/day in 1-2 days and lowered blood pressure in a woman and in her 2 1/2-yr-old daughter, both of whom have hypertension and hyporeninemia and are members of a kindred with dexamethasone-suppressible aldosteronism. ACTH given for 7 days produced a sustained increase in aldosterone production and a rise in blood pressure in both patients. The abnormal suppression with dexamethasone and further stimulation with ACTH indicate that the aldosteronism is ACTH-dependent in this disorder. The cause of the ACTH-dependence of aldosterone production in this disorder is unknown but may represent continued stimulation rather than the usual (secondary) inhibition by ACTH of 11-hydroxylation and 18-hydroxylation in zone glomerulosa cells. Blood pressure was normal during treatment with spironolactone and during pregnancy, when the action of aldosterone and other similar steroids was presumably blocked by an increased production of progesterone; this suggests that the hypertension is dependent upon sodium-retaining steroids such as aldosterone. Aminoglutethimide given during treatment with ACTH decreased urinary aldosterone and blood pressure and increased PRA, with minimal effects on plasma cortisol or urinary 17-hydroxycorticosteroids. These results provide additional evidence that aldosterone, acting alone or in conjunction with other steroids synthesized by the zona glomerulosa, mediates the hypertension and hyporeninemia of dexamethasone-suppressible aldosteronism.

High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension.

Dopamine in urine is derived substantially from renal uptake and decarboxylation of 3,4-dihydroxyphenylalanine (dopa), and increases in excretion of dopa normally parallel increases in excretion of dopamine during salt loading. Since patients with salt-sensitive hypertension may have decreased urinary excretion of dopamine during dietary salt loading, the present study was designed to evaluate the response of dopa to salt loading. Sixteen inpatients with normal-renin essential hypertension ate a constant metabolic diet containing 9 mmol/day sodium for 7 days, followed by the same diet but containing 249 mmol/day sodium for 7 days. Salt sensitivity was defined as an increase in mean arterial pressure of 8 mm Hg between the diets; on this basis, nine patients were salt-sensitive and seven, salt-resistant. The rate of urinary dopa excretion was significantly higher in the salt-sensitive patients throughout the study (mean rates 132 +/- 13 nmol/day in the salt-sensitive group and 78 +/- 9 nmol/day in the salt-resistant group for the 14 days of observation, p less than 0.01). When dietary sodium intake was increased to 249 mmol/day, urinary dopa excretion increased significantly more in salt-sensitive patients than salt-resistant patients. At the end of the high salt diet, dopamine excretion was significantly attenuated in the salt-sensitive patients, despite higher rates of dopa excretion. Thus, the urinary ratio of dopamine to dopa was decreased in salt-sensitive patients, regardless of salt intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension.

Nineteen patients with normal renin idiopathic hypertension were arbitrarily classified as salt-sensitive or salt-resistant depending on whether their mean arterial pressure did or did not increase by 8% or more when sodium intake was increased. The responses of the two subsets and of five normal subjects to sodium intakes of 9, 109, and 249 mEq/day given for 7 days were as follows: The salt-sensitive subjects retained more sodium than normal and plasma or urinary norepinephrine did not decrease when they were given a high sodium intake; urinary dopamine was normal but did not increase normally when sodium intake was increased. The salt-resistant subjects excreted sodium normally and plasma and urinary norepinephrine was decreased by 30 and 37%, respectively, when they were given a high sodium intake; urinary dopamine was supernormal and did not increase further when sodium intake was increased. Cumulative sodium retention during the high sodium intake was directly related to the percentage of change in plasma norepinephrine in the hypertensive subjects, suggesting that renal adrenergic activity was a factor in the impaired sodium excretion in the salt-sensitive patients. Cumulative sodium retention and the percentage of change in plasma norepinephrine were inversely related to urinary dopamine in the hypertensive subjects, suggesting that increased formation of dopamine in renal and neural tissue in the salt-resistant subjects may have been responsible for the differences between the subsets in renal and adrenergic responses to a high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid-suppressible aldosteronism: a disorder of the adrenal transitional zone.

Glucocorticoid-suppressible aldosteronism (GSA) is a rare form of hyperaldosteronism in which the increased secretion of aldosterone and the elevation of blood pressure are corrected when ACTH secretion is suppressed. Two 17-hydroxylated analogs of 18-hydroxycorticosterone and aldosterone, 18-hydroxycortisol and 18-oxocortisol, which had been identified in the urine of patients with hyperaldosteronism due to an adrenal adenoma and in bullfrog adrenal tissue incubated with cortisol, are produced in greater than normal quantities in patients with GSA. The excretion of 18-hydroxycortisol and 18-oxocortisol in nine patients with GSA was 2914 +/- 923 (+/- SD) nmol/day [1108 +/- 351 micrograms/day; normal, 165 +/- 94 nmol/day (63 +/- 36 micrograms/day)] and 141 +/- 77 nmol/day [53 +/- 29 micrograms/day; normal, 3.2 +/- 2.4 nmol/day (1.2 +/- 0.9 micrograms/day)], respectively. The excretion of aldosterone 18-oxoglucuronide was 53 +/- 18 nmold/day [19.4 +/- 6.8 micrograms/day; normal, 16.9 +/- 7.5 nmol/day (6.1 +/- 2.7 micrograms/day)]. Aldosterone excretion was elevated in six patients and within the normal range in three patients. The degree of abnormality in 18-hydroxycortisol and 18-oxocortisol excretion was significantly greater than that in aldosterone. Dexamethasone administration decreased excretion of the three steroids to the normal range. ACTH administration for 3 days resulted in an exaggerated increase in the excretion of these steroids, suggesting ACTH dependence of these steroids in patients with GSA. The excessive production of these steroids, which are 17- and 18-hydroxylated, indicate that they are produced by hybrid-type cells which we have called transitional cells, which are also capable of producing aldosterone. These findings are consistent with the postulate that cytochrome P-450-corticosterone methyl oxidase fails to disappear normally in the zona glomerulosa cells as they migrate to the zona fasciculata and acquire 17-hydroxylase activity. This abnormality explains the supernormal conversion of cortisol to 18-hydroxycortisol and 18-oxocortisol and the ACTH dependence of aldosterone secretion in GSA.

Plasma immunoreactive proopiolipomelanocortin-derived peptides in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism.

Immunoreactive plasma levels of the proopiolipomelanocortin-derived peptides, ACTH, beta-endorphin-lipotropin, and gamma 3MSH, were measured in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, infusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism.