Hyponatremia due to cerebral salt-wasting syndrome: Combined cerebral and distal tubular lesion

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt wasting in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted In a normal serum sodium level and blood pressure. This case falls in the category of “cerebral salt wasting” syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.     

Production of triiodothyronine in normal human subjects and in patients with hyperthyroism. Contribution of intrathyroid iodine analysis

Alexander Gutman was a pioneer in measuring total iodine and L-thyroxine (T₄) concentrations within the thyroid gland nearly 50 years ago. On this foundation, new analytical technics developed in the intervening years greatly expanded knowledge of intrathyroid hormone content. This review examines how the latter has contributed to the understanding of the physiology and physiopathology of specific problems currently of great Interest in thyroid research; namely, the source of circulating triiodothyronine (T₃) in normal man and the course of a newly described clinical entity, T₃-toxicosis.The recent conclusive demonstration of the peripheral conversion of T₄ to T₃ in man raises the question of the proportion of total T₃ production normally derived from this pathway, as opposed to direct thyroid secretion. Direct analyses of T₄ to T₃ ratios in human thyroid tissue suggest that relatively little T₃ is derived directly from the thyroid; however, the inhomogeneity of intrathyroidal iodine pools, and the possibility that T₄ may be converted to T₃ within the thyroid, make this approach of limited value. The problem will be settled only by careful kinetic analyses making possible a comparison between the total T₃ production rate and that derived from peripheral T₄ deiodination.T₃ toxicosis is a recently described entity in which hyperthyroidism is associated with an increased serum T₃ concentration, together with a normal or decreased concentration of T₄. In the usual form of thyrotoxicosis, in which both T₄ and T₃ levels are elevated, the thyroid also secretes disproportionately large quantities of T₃ relative to T₄. Since there is evidence in animals and man that iodine deficiency favors synthesis and secretion of T₃ relative to T₄, the relative-hypersecretion of T₃ in both varieties of thyrotoxicosis may reflect a relative intrathyroid iodine deficiency. That this possibility is more than speculative is suggested by Gutman's early finding of a decrease in the total iodine and T₄ content of thyrotoxic glands. The mechanism whereby intrathyroid iodine depletion may occur in the thyrotoxic gland remains obscure, however.     

Renal failure after major angiography

A recently reported 12 per cent incidence of renal failure following angiography prompted our prospective study to substantiate or repudiate this seemingly excessive rate. In 100 consecutive patients, there was no instance of renal failure following angiography. The results of our study indicate that when adequate hydration is maintained angiography does not pose a “significant hazard” of renal failure as previously reported, even in patients with underlying medical problems.     

Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients

Seven elderly patients were encountered who had been taking thiazides or thiazide-like diuretics (hydrochlorothiazide, polythiazide or metolazone) for less than 16 days and who presented with severe symptomatic hyponatremia (serum SODIUM = 105 ± 6 meq/liter). In five patients, urine sodium + potassium was 156 meq/liter whereas that in serum was 108 meq/liter (P < 0.01). All patients had central nervous manifestations of hyponatremia (seizures, stupor, coma, extensor plantar response) and all but one were treated with 3 percent sodium chloride to raise the serum sodium level above 130 meq/liter within 44 hours. Three patients died, two had permanent paralysis, and two recovered. Other causes of the neurologic dysfunction were ruled out by negative lumbar punctures, brain scan and computerized axial tomography (CAT) scan. In all, serum creatinine was below 1.1 mg/dl.

The patients who recovered were studied. In two patients, the administration of oral metolazone (10 mg/day for two days) or hydrochlorothiazide (100 mg/day for two days) with ad libitum water intake resulted in decrements in serum sodium of 13 to 18 meq/liter in 36 hours. In both, serum sodium levels fell below 125 meq/liter with resultant symptoms. In one patient, the response to a standard oral water loading test was studied before and after 10 mg of metolazone administration. After metolazone therapy, the percent excretion of a standard oral water load in 4 hours fell from 65 percent to 15 percent, minimal urine osmolality, which had been 130 to 371 mosmol/kg, increased to 371 mosmol/kg, free water clearance fell from 2.25 to −0.25 ml/min and urine sodium excretion increased from 62 to 159 μeq/min. Plasma antidiuretic hormone (ADH) levels were undetectable before and after the administration of metolazone but rose after overnight dehydration. Thus, metolazone resulted in impaired ability to dilute the urine and excrete a water load, with 256 percent increase in urine sodium loss. Therefore, in a susceptible subgroup of outpatients, thiazides may rapidly induce severe hyponatremia with permanent neurologic damage or death.     

Central nervous system manifestations of hyperparathyroidism

Prospective neurologic and psychologic studies were thus undertaken in 19 patients who were to undergo major neck operations either for parathyroidectomy (seven for primary hyperparathyroidism and six for secondary hyperparathyroidism) or other reasons (six control subjects). A complete physical and neurologic examination, laboratory tests (calcium, PTH), roentgenograms, a standard electroencephalogram and psychologic testing were carried out in patients before and three and a half months after neck operation.The preoperative electroencephalograms were abnormal in groups with both primary and secondary hyperparathyroidism. For the patients with primary hyperparathyroidism, the preoperative electroencephalogram revealed a percentage electroencephalographic power below 5 Hz (± SE) of 4.2 ± 2.2 per cent (normal = 2.4 ± 1.0 per cent), and the percentage of electroencephalographic frequencies below 7 Hz was 14.7 ± 3.2 per cent (normal = 6.0 ± 1.6 per cent). Postoperatively, however, there were significant (p < 0.01) decrements in these measurements to normal values. The percentage electroencephalographic power below 5 Hz was 1.5 ± 0.6 per cent, whereas the percentage of electroencephalographic frequencies below 7 Hz was 5.2 ± 1.1 per cent. In patients with secondary hyperparathyroidism, both the percentage electroencephalographic power below 5 Hz (9.7 ± 2.5 per cent, p < 0.01) and the percentage electroencephalographic frequencies below 7 Hz (22.2 ± 4.2 per cent, p < 0.01), were significantly higher than normal values. There were significant decrements in all the abnormal electroencephalographic values postoperatively. The percentage electroencephalographic power below 5 Hz decreased to 3.4 ± 2.4 per cent, and the percentage electroencephalographic frequencies below 7 Hz decreased to 17.4 ± 3.1 per cent. Electroencephalograms in control patients did not change.Patients with primary hyperparathyroidism showed no significant postoperative improvement in any of the psychologic parameters tested. By contrast, patients with secondary hyperparathyroidism showed improvement in several areas of testing after undergoing surgery when compared to control subjects.The brain calcium in four other patients with secondary hyperparathyroidism who died of miscellaneous causes was 38.3 ± 5.7 meq/kg dry wt, versus the normal value of 25.2 ± 0.7 meq/kg dry wt (p < 0.03).These data show that in patients with either primary or secondary hyperparathyroidism, the electroencephalogram is abnormal and shows significant improvement following parathyroidectomy. There is also improvement in several tests of intellectual function in patients with secondary hyperparathyroidism. Brain calcium content was significantly higher than normal in patients with secondary hyperparathyroidism.     

Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis. Evidence for selective distal tubular dysfunction.

A 61 year old male patient was studied who manifested dehydration, azotemia, acidosis and hyperkalemia six weeks after exposure to methicillin. Thyroid and adrenal glucocorticoid and mineralocorticoid function were normal. The dehydration was found to be caused by a profound sodium-losing nephropathy; urinary sodium ranged from 78 to 101 meq/day during a salt restricted diet. A distal renal tubular acidosis and a quantitively impaired ability to excrete potassium were also found. These defects were relatively unresponsive to mineralocorticoid or prednisone therapy. A renal biopsy specimen showed an interstitial nephritis which selectively affected distal tubules and was thought to be secondary to methicillin. The data suggest functional impairment specific for the distal tubule, but with only a modest decrease in the glomerular filtration rate.     

Detection and quantification of previous myocardial infarction by exercise-redistribution tomographic thallium-201 scintigraphy

Although myocardial perfusion scintigraphy at rest accurately diagnoses myocardial infarction (MI), the prevalence and size of previous MI is overestimated by exercise-redistribution thallium-201 studies. A new, quantitative approach to the analysis of tomographic thallium-201 scintigrams was developed in order to determine whether the presence and extent of MI could be determined. Sixty patients undergoing cardiac catheterization for chest pain syndromes, including 28 with previous MI, were studied by exercise and 3-hour delayed thallium-201 scintigraphy, with use of the 7-pinhole tomographic technique. Circumferential profiles of the postexercise and 3-hour radiotracer distribution were generated from apical, midventricular and basal left ventricular slices. The 3-hour profile fell below normal limits in 24 of 28 patients (86%) with remote MI, but was also abnormal in 9 of 22 patients (41%) with coronary disease but no MI. All missed MIs were either inferior or subendocardial and were associated with normal ejection fractions. To distinguish between MI and slowly resolving ischemic defects, a quantitative approach was used. MI area was calculated as the area in which the 3-hour profile fell below the 3-hour normal limits, and a redistribution area in the MI zone was determined as the area between the postexercise and 3-hour profiles in the region where the 3-hour profile was abnormal. The MI area was 1,000 +/- 980 units in patients with MI, vs 79 +/- 120 units in patients without MI (p less than 0.001), whereas the redistribution area was higher in patients without MI (1,240 +/- 810 vs 430 +/- 400 units, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial metabolic alterations after contrast angiography

Contrast media used during angiography are known to produce transient alterations in cardiovascular physiology. However, little information is available concerning what alterations, if any, occur in myocardial metabolism after contrast angiography. Sixteen patients with symptoms of ischemic heart disease undergoing elective left ventriculography were studied. Coronary sinus and arterial blood samples were obtained for free fatty acids, glucose and lactate before and after performing left ventriculography with Renografin-76. Coronary blood flow was determined by the thermodilution technique. Five minutes after ventriculography, the arterial level of free fatty acids had decreased by 18.0 ± 4.9 percent (mean ± standard deviation) from the baseline (before angiography) samples (probability [p] < 0.001). Associated with this decrease in arterial free fatty acids was an increase in the myocardial uptake of this substrate. At 5 minutes after left ventriculography, the free fatty acid uptake had increased 48.5 ± 33.0 percent compared with the baseline value (p < 0.001). After the injection of contrast medium, there was no significant change in the arterial levels of glucose or lactate. However, significant decreases in the myocardial uptake of glucose and lactate were demonstrated ( ?72.5 ± 44.5 percent [p < 0.001] and ?43.2 ± 22.9 percent [p < 0.001], respectively) at 5 minutes. The changes in arterial free fatty acids and in the myocardial uptake of the various substrates persisted throughout the sampling period of 20 minutes after ventriculography. These results demonstrate that contrast medium significantly alters myocardial metabolism. These metabolic alterations persist longer than the hemodynamic changes induced by contrast angiography.     

Improved radiation protection for physicians performing cardiac catheterization

Physicians and their assistants performing diagnostic angiography must be concerned with the radiation exposure they receive. The introduction of hemiaxial projections for imaging has increased diagnostic accuracy but has also greatly increased the physicians' exposure to scattered radiation. This increase is especially critical for the eyes and thyroid of the physician who routinely performs these procedures. To reduce such exposure a ceiling-suspended shield (60 × 45 cm), made of 6.4 mm glass with a 19.5 kg/m² (4 lb/ft²) lead equivalency, was developed. During procedures the shield is interposed between the physician and the region of the patient acting as the source of scattered radiation. The degree of radiation protection to the operator was assessed by measuring the distribution of scattered radiation in the vicinity of the operator with and without the shield. The effectiveness of the shield was determined in the 30 ° right anterior oblique (RAO), 5 ° left anterior oblique (LAO), 35 ° LAO, and 50 ° LAO-15 ° cranial angulations. At critical heights such as the level of the eyes and thyroid, scattered radiation levels were reduced by 85% or greater in all angulations. Without interfering with the physician's ability to observe the patient or manipulate the catheter, this shield can significantly reduce the physician's exposure to radiation.     

Failure of antihypertensive therapy with diuretic,beta-blocking and calcium channel-blocking drugs to consistently reverse left ventricular diastolic filling abnormalities

The present protocol was designed to determine whether antihypertensive therapy with hydrochlorothiazide, propranolol or diltiazem, 3 agents with different mechanisms of action and potentially different effects on myocardial function, reverses left ventricular filling abnormalities. Twelve patients with essential hypertension and no evidence of associated cardiovascular disease, either clinically or with noninvasive testing, were evaluated while taking no medication and after 2 months of treatment with these agents. All 3 drugs produced equivalent control of blood pressure (BP), reducing sitting systolic BP by a mean of 20 to 24 mm Hg and diastolic BP by 14 to 16 mm Hg. LV ejection fraction and end-diastolic volume were normal in all but 1 subject (who was excluded from the analyses of LV diastolic filling) and were not altered by drug therapy. The peak LV filling rate and the first-third filling fraction were reduced in the patients with hypertension, but neither of these indexes nor the time to peak filling rate were significantly improved for the group as a whole by any of these medications. Nine of 10 patients whose BP was controlled by diltiazem had increases in their first-third filling fraction, but this change did not reach statistical significance. Our findings suggest that abnormalities of LV diastolic filling are not consistently affected by short-term therapy in patients with chronic, previously treated systemic hypertension.     

Dual carbon-labeled isotope experiments using D-[6-14C] glucose and L-[1,2,3-13C3] lactate: a new approach for investigating human myocardial metabolism during ischemia

Simultaneous lactate production and extraction have been previously demonstrated in the myocardium in patients with coronary artery disease. To quantitate this lactate production and determine its source, dual carbon-labeled isotope experiments were performed. L-[1,2,3-13C3] lactate and D-[6-14C] glucose were infused in 10 patients with significant coronary artery disease. Metabolic samples were obtained at rest and during atrial pacing. Despite net chemical myocardial lactate extraction in the 10 patients at rest and no evidence of clinical ischemia, the L-[1,2,3-13C3] lactate analysis demonstrated that lactate was being released by the myocardium. During atrial pacing, seven patients did not develop clinical symptoms of ischemia, and the chemical lactate analysis showed net lactate extraction. However, tracer analysis demonstrated that there was a significant increase in the lactate released during atrial pacing (from 6.9 +/- 2.3 to 16.2 +/- 10.1 mumol/min) (p less than 0.05). In these seven patients, circulating glucose was the source of 23 +/- 15% of the lactate released at rest, and there was no significant change during pacing. The remaining three patients had mild chest pain and net chemical lactate production during pacing. Lactate release detected by the tracer increased from 5.7 +/- 3.0 mumol/min at rest to 50.9 +/- 16.8 mumol/min during pacing (p less than 0.01). In these patients, the contribution of glucose to lactate production increased significantly during pacing-induced clinical ischemia from 25 +/- 22 to 67 +/- 14% (p less than 0.005). Thus, dual carbon-labeled isotopic experiments are powerful tools for investigating myocardial metabolic pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of uremia on circulating mevalonate metabolism in rats

Mevalonate, an essential intermediate in cholesterol synthesis, is metabolized either to sterols or by the shunt pathway to CO₂. Previous studies have demonstrated that the kidneys are the chief site of circulating mevalonate metabolism by both pathways. Following nephrectomy, as expected, the shunt pathway was reduced by greater than 50%. However, nephrectomy resulted in an enhancement of total body sterologenesis which was due to a marked stimulation of both liver and carcass sterol synthesis. The present study unexpectedly demonstrates that, even in the presence of intact kidneys, uremia induces marked alterations in the metabolism of circulating mevalonate that are similar to those observed following nephrectomy. In rats with normal renal mass the oxidation of mevalonate to CO₂ is reduced by 57% in acutely uremic and by 34% in chronically uremic animals. This reduction in shunt pathway activity directly correlates with the degree of impairment of renal function as measured by plasma BUN and creatinine levels. In contrast to the inhibition of the shunt pathway, acute and chronic uremia is associated with a two- to threefold increase in both hepatic and carcass cholesterol and nonsaponifiable lipid synthesis from circulating mevalonate. In the liver this enhancement of sterologenesis directly correlates with plasma BUN and creatinine concentrations. Renal sterologenesis from circulating mevalonate is not significantly altered by either acute or chronic uremia. This study demonstrates that uremia per se greatly alters circulating mevalonate metabolism resulting in a marked reduction in the shunt pathway and a large stimulation of sterol synthesis in both the liver and carcass.     

Improved efficacy of high-dose versus medium- and lowdose diltiazem therapy for chronic stable angina pectoris

The efficacy of therapy with diltiazem, 360 mg/day, was studied in 11 men with chronic, stable angina pectoris. An initial dose-titration schedule in which diltiazem was increased weekly from placebo to 120, 240 and 360 mg/day (Period I) was followed by a randomized, double-blind, 1-month crossover trial of placebo vs diltiazem at 360 mg/day (Period II). A computer-assisted treadmill exercise test was performed at the end of each dose and each 2-week crossover period. Diltiazem at 360 mg/day, compared with placebo (Period II), significantly improved exercise performance. Exercise duration to onset of chest pain increased 40% from 5.3 ± 2.1 to 7.4 ± 2.7 minutes (p < 0.01). Time to reach 1 mm of ST-segment depression increased 33%, from 5.1 ± 2.0 to 6.8 ± 1.8 minutes (p < 0.01). Total exercise duration increased 16%, from 7.5 ± 2.0 to 8.7 ± 2.0 minutes (p < 0.005). A computer-derived quantitative treadmill exercise score improved 27%, from ? 13.1 ± 9.4 to ? 9.5 ± 7.6 units (p < 0.005), and the ST-segment depression at peak exercise improved from ? 1.9 ± 1.1 to ? 1.6 ± 1.2 mm (p < 0.05). Progressive improvement in these variables was seen during the single-blind dose-titration period between 120 and 240 mg/day and between 240 and 360 mg/day (Period I). Baseline heart rate (HR) and diastolic blood pressure (BP) in the supine and upright position were significantly lower with diltiazem than with placebo. Diltiazem decreased the supine HR at rest from 67 ± 14 to 60 ± 10 beats/min (p < 0.05) and the upright HR at rest from 77 ± 14 to 69 ± 13 beats/min (p < 0.005). Diastolic BP at rest in the supine position decreased from 81 ± 6 to 75 ± 7 mm Hg (p < 0.05) and in the upright position from 82 ± 9 to 76 ± 8 mm Hg (p < 0.05). Thus, diltiazem improved exercise tolerance and exerciseinduced myocardial ischemia and showed good dose-response characteristics at doses as high as 360 mg/day in patients with stable angina pectoris.     

The mechanism of recovery of hepatic T4-5'-deiodinase during glucose-refeeding: role of glucagon and insulin

Refeeding studies were performed on male Sprague-Dawley rats that had been fasted for 72 hours to characterize the specific effect of carbohydrates on T₃ metabolism. Fasting is associated with low serum T₃ levels and reduced hepatic T₄-5′-deiodinase activity (T₄ → T₃). Carbohydrate refeeding (20% glucose in H₂O) normalized both the serum T₃ and hepatic T₄-5′-deiodinase activity within 72 hours, whereas fat (10% Intralipid) and amino acids (5.5% Travasol) had no effect after 72 hours of refeeding. Refeeding with a mixed diet (Purina Rodent Chow) occasionally reactivated hepatic T₄-5′-deiodinase activity, however, normalization of enzyme activity did not occur within 72 hours. Time-course studies demonstrated that hepatic T₄-5′-deiodinase activity was not stimulated until 24 hours of carbohydrate refeeding had elapsed and that 48 to 72 hours were required for normalization. The mechanism of the carbohydrate-refeeding effect was characterized by analyzing the alterations in the kinetics Michaelis constant (Km) and maximal velocity (Vmax) of hepatic T₄-5′-deiodinase and the changes in the hepatic content of nonprotein sulfhydryl groups (NP-SH), which are possible enzyme cofactors. There was no relationship between the hepatic enzyme activity and the NP-SH response during the refeeding period. Moreover, homogenate enrichment with the sulfhydryl compound, dithiothreitol (DTT), did not alter the temporal profile of the enzyme recovery consequent to refeeding. Refeeding with carbohydrate had no effect on the Km of hepatic T₄-5′-deiodinase but had a significant effect on the Vmax. Refeeding with glucose induced an increase in enzyme Vmax over the time-course, which became significant (P < 0.005) compared with the enzyme Vmax of the fasted group by 72 hours. During carbohydrate refeeding, a positive correlation was noted between the ratio of serum insulin to glucagon and hepatic-T₄-5′-deiodinase activity (r = 0.82, P < 0.001), whereas a negative correlation was found between enzyme activity and the ratio of serum glucose to insulin (r = ?0.9, P < 0.001). Furthermore these correlations also applied during refeeding with fat and amino acids. Thus, the carbohydrate-refeeding reactivation of hepatic T₄-5′-deiodinase in fasted rats is a delayed process that requires a refeeding period equivalent to the duration of fasting for enzyme normalization to occur. Recovery was due to an increase in the hepatic content of active enzyme rather than an enhancement of cofactor supply. The glucoregulatory hormones, glucagon and insulin, may modulate these carbohydrate induced changes on hepatic T₄-5′-deiodinase. Moreover, the differential reaction of hepatic T₄-5′-deiodinase to specific nutriments may be mediated by these glucoregulatory hormones.     

Glucose metabolism and insulin sensitivity in patients on chronic hemodialysis

In order to evaluate the potential role of parathyroid hormone on glucose metabolism in patients on chronic hemodialysis hyperglycemic clamp studies were performed in 7 parathyroidectomized and 11 nonparathyroidectomized patients on chronic hemodialysis and in healthy controls. There were no significant differences in the peripheral glucose uptake of the 3 groups. The beta cell response to hyperglycemia during the early phase as well as during the steady state was almost identical in controls and in nonparathyroidectomized uremics, whereas in the parathyroidectomized group a markedly enhanced insulin secretion was found. Calculated tissue sensitivity to insulin therefore was equal in controls and in nonparathyroidectomized uremics, whereas patients after parathyroidectomy had peripheral insulin resistance. Our results demonstrate that patients on chronic hemodialysis apparently have normal peripheral glucose uptake. The subgroup of patients who have undergone parathyroidectomy, however, show an enhanced insulin response to hyperglycemia suggesting peripheral insulin resistance. We conclude that longstanding and severe secondary hyperparathyroidism--the usual cause for parathyroidectomy in these patients--results in irreversible insulin resistance with a compensatory increase of insulin secretion.     

Monotherapy in mild to moderate hypertension: Comparison of hydrochlorothiazide,propranolol and prazosin

There has been recent interest in using nondiuretic drugs as initial antihypertensive therapy. Therefore, a study was designed to compare the efficacy and the effects on left ventricular function of hydrochlorothiazide, propranolol and prazosin in 13 patients with mild to moderate hypertension. After a 4-week washout period, patients were treated serially with each drug in a randomized order for 2 months each. Dosages were titrated until the patient showed a sitting diastolic blood pressure ≤90 mm Hg or to a maximum dosage of 100 mg/day of hydrochlorothiazide, 320 mg of propranolol and 20 mg of prazosin. Blood pressure was measured, plasma catecholamine concentrations were assayed and radionuclide determinations of rest and exercise left ventricular function and volume were made at the end of each period as well as after a second 1-month washout period at the end.In the sitting and standing positions, systolic and diastolic blood pressure control was equivalent for all 3 drugs. Goal blood pressure was achieved in 10 of 13 patients receiving hydrochlorothiazide, in 8 of 12 receiving propranolol and in 9 of 13 on prazosin. Importantly, 3 of 4 patients not controlled with prazosin, 5 of 6 uncontrolled with propranolol and 2 of 3 whose blood pressure was not reduced by hydrochlorothiazide were controlled when receiving 1 of the other medications. None of the drugs changed rest or exercise ejection fraction or volume, and side effects were minimal. These findings indicate that as single agents, all 3 drugs produce similar effects on blood pressure, have few symptomatic side effects and can effectively be substituted for each other when there is a lack of efficacy or contraindication to 1 drug.