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(Hypertension. 1996;28:335-340.)
© 1996 American Heart Association, Inc.

Articles

Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension

Vito M. Campese; Medhat Tawadrous; Roberto Bigazzi; Stefano Bianchi; Amardeep S. Mann; Suzanne Oparil; Leopoldo Raij

the University of Southern California, Los Angeles (V.M.C., A.M.); Unita' Operativa, Livorno, Italy (R.B., S.B.); University of Alabama, Birmingham (S.O.); and VA Medical Center, University of Minnesota, Minneapolis (L.R.).

Correspondence to Vito M. Campese, MD, LAC/USC Medical Center, 2025 Zonal Ave, Los Angeles, CA 90033.

	Abstract

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In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO₂+NO₃ in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P<.01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO₂+NO₃ levels were higher (P<.05) in salt-sensitive (189±7.9 µmol/L) and salt-resistant (195±13.5 µmol/L) black patients than in control subjects (108±9.7 µmol/L). During high salt intake, plasma NO₂+NO₃ decreased significantly (P<.01) in both salt-sensitive (150±7.0 µmol/L) and salt-resistant (142±9.0 µmol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

Key Words: natriuretic peptides • nitric oxide • hypertension, sodium-dependent • sodium, dietary • endothelium-derived factor • blacks

	Introduction

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Individuals with essential hypertension manifest variable blood pressure responses to high dietary salt (NaCl) intake and, accordingly, are classified as salt-sensitive or salt-resistant.¹ The prevalence of salt sensitivity is greater in blacks than in whites.² Salt-sensitive patients manifest an abnormal renal function curve, greater propensity to retain sodium (Na⁺), and abnormal renal hemodynamic adaptation to high NaCl intake.³ These abnormalities have been attributed to increased secretion of pressor hormones, decreased secretion of vasodilators, or both. Some studies indicate that Na⁺ retention and blood pressure sensitivity to NaCl load are due to increased activity of the sympathetic nervous system.^{4 5 6 7} Other studies have shown that salt sensitivity may be due to reduced production of vasodilators such as dopamine⁸ and kallikrein.^{9 10 11} Little attention has been paid to the possibility that salt sensitivity might be due to impaired modulation of endogenous vasodilators, such as atrial natriuretic peptide (ANP) and nitric oxide (NO).

ANP is produced mainly in the cardiac atria and released into the circulation in response to volume expansion and increased atrial distention.^{12 13} ANP interacts with specific receptors in the vasculature and kidney, resulting in lower blood pressure and increased urinary Na⁺ excretion. In high doses, ANP infusion decreases blood pressure and increases urinary Na⁺ excretion.¹⁴ In low doses, enough to achieve plasma levels twofold those of basal levels, ANP causes natriuresis but no change in blood pressure unless the infusion is sustained for a prolonged time.^{15 16} The role of ANP in blood pressure regulation and the pathogenesis of hypertension in humans has recently been reviewed.¹⁷ A reduction of ANP secretion could result in Na⁺ retention and salt-sensitive hypertension. This possibility is supported by studies showing that a disruption of the proANP gene in mice causes salt-sensitive hypertension.¹⁸

NO is a vasodilator identical to or closely related to the endothelium-derived relaxing factor. NO is synthesized from L-arginine by a family of NO synthases.^{19 20} NO activates guanylyl cyclase, increasing the levels of cytoplasmic GMP.²¹ This reduces the flow of calcium into cells and results in vasodilatation.²² Recent studies have shown that NO may cause vasodilatation by activation of a Ca²⁺-dependent K⁺ channel.²³

Abnormal endothelial function has been described in many experimental models of chronic hypertension.^{24 25 26 27} Transgenic mice lacking the endothelial NO synthase are mildly hypertensive.²⁸ Recent studies in rats with genetic hypertension have demonstrated that synthesis of endothelium-dependent contracting factors is increased. In the same rats, vascular production of NO is also increased, perhaps as a compensatory response.²⁹ The vasoconstrictor response to N^G-monomethyl-L-arginine was found to be impaired, and the degree of impairment was correlated with blood pressure.³⁰ Some researchers have shown a normal vasodilator response,³¹ whereas others have shown an abnormal response to acetylcholine in patients with essential hypertension.^{32 33 34} Accordingly, it is unclear whether endothelial dysfunction uniformly occurs in individuals with essential hypertension and whether NO deficiency plays a role in the development and/or maintenance of hypertension. It is possible that the production of NO may vary in different stages of hypertensive vascular disease.

The interrelations between dietary salt intake and endothelial function have not been adequately investigated. In normotensive rats, dietary salt loading enhances NO production, measured by the excretion of NO₂ and NO₃ as well as cGMP,³⁵ but does not affect NO production in the hindquarter circulation.³⁶ In Dahl/Rapp salt-resistant rats, ingestion of a high NaCl diet impairs the myogenic response of renal afferent arterioles³⁷ and the dilation of large cerebral collateral arterioles in response to cerebral occlusion,³⁸ two hemodynamic responses thought to be endothelium dependent. In addition, high dietary NaCl intake attenuates the flow-dependent arteriolar dilation in rat spinotrapezius muscle, an action partly mediated by endogenous NO.³⁹ In all, these studies suggest that high NaCl intake may suppress NO activity in the peripheral resistance vessels. Exogenous L-arginine, the substrate for NO synthase, decreases blood pressure to normotensive levels in Dahl/Rapp salt-sensitive rats, but it does not alter blood pressure in spontaneously hypertensive rats⁴⁰ or peripheral vascular resistance in hyperten-sive humans.⁴¹

In humans with essential hypertension, the role of endothelium-derived relaxing factor or NO in the blood pressure sensitivity to dietary salt intake has not been investigated.

The current study tested the hypothesis that ANP and NO release in response to high dietary NaCl intake may be altered and contribute to salt sensitivity in hypertensive individuals. To test this hypothesis, we measured blood levels of ANP and NO₂ and NO₃ (NOx), stable metabolites of NO, in normotensive subjects and hypertensive patients during low and high NaCl intakes. To exclude the possibility of racial differences in ANP secretion, we studied both black and white hypertensive patients.

	Methods

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Thirty-four blacks and 14 whites were included in the studies. Twenty-seven blacks had hypertension and 7 were normotensive. All 14 whites were hypertensive. Demographic characteristics are shown in Tables 1 and 2.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Black Patients With Essential Hypertension and Normotensive Control Subjects

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of White Patients With Essential Hypertension

Patients with a history of myocardial infarction, congestive heart failure, stroke, creatinine clearance less than 80 mL/min, diabetes mellitus, or liver disease were excluded. Women with childbearing potential or on birth control pills and individuals known to abuse drugs or alcohol were also excluded. Patients were considered to be hypertensive if during three consecutive visits to the outpatient clinic, they had blood pressure equal to or greater than 140/90 mm Hg. Antihypertensive medications were discontinued at least 2 weeks before the study. A diagnosis of secondary hypertension was ruled out by the presence of normal routine blood chemistry, urinalysis, and chest radiograph. When clinically indicated, we measured urinary metanephrines to rule out a diagnosis of pheochromocytoma, measured plasma aldosterone to rule out primary aldosteronism, and performed a renal angiogram to exclude renovascular hypertension. Patients with secondary hypertension were excluded.

The studies were approved by the Research Committees of the Los Angeles County–University of Southern California Medical Center and of the Unita' Operativa in Livorno, Italy. All blacks were studied at the University of Southern California, and all whites were studied in Italy. After the nature and purpose of the study had been explained and informed consent was obtained, all blacks were admitted to the Clinical Research Center of the Los Angeles County–University of Southern California Medical Center for 23 days. Throughout the study, the subjects ingested the same basic diet containing constant amounts of protein (1.3 g/kg body wt), calories (30 kcal/kg body wt), calcium (800 mg/24 h), and potassium (80 mEq/d), while their Na⁺ intake varied. During the first 6 days of the study, all subjects received 20 mEq/d Na⁺, and during the following 6 days, they received a dietary Na⁺ intake of 250 mEq/d. The subjects were weighed daily at 8 AM, after they had voided and before they ate breakfast. Twenty-four-hour urine samples were obtained daily throughout the study for measurement of creatinine, sodium, and potassium.

The studies in whites were done at the Unita' Operativa in Livorno, Italy, where, because of the lack of availability of a Clinical Research Center, the patients were hospitalized only the last day of each dietary regimen. Patients were instructed to adhere for 2 weeks to an isocaloric diet containing 1.3 g/kg protein, 30 kcal/kg body wt in calories, 800 mg/d calcium, and 80 mEq/d potassium while their sodium intake varied. During the first week, they received a diet containing 20 mEq/d Na⁺, and during the remaining 7 days, they received a dietary Na⁺ intake of 250 mEq/d. The food was prepared by the hospital kitchen and provided to the patients on a daily basis. Compliance to the prescribed diet was assessed by measurement of 24-hour urinary Na⁺ excretion during the last 2 days of each diet. Blood pressure and body weight were measured at the beginning and on days 6 and 7 of each diet between 8 and 9 AM. Patients were weighed after they had voided and before they ate breakfast.

On the last day of each dietary Na⁺ regimen and after fasting overnight, the subjects included in both studies assumed the recumbent position between 7 and 8 AM, and a venous catheter was inserted into a forearm. One hour later, blood pressure and heart rate were measured and blood samples obtained for determination of serum sodium, potassium, and creatinine; hematocrit; ANP; and NO₂+NO₃. All subjects ate their breakfast after they had completed the study.

Blood pressure was measured with an automatic recorder (Omega 1000, Invivo Research Laboratories, Inc). Each data point of blood pressure is the mean of at least three consecutive readings. Mean arterial pressure (MAP) was calculated as the sum of diastolic pressure and one third of pulse pressure. Sodium and potassium were determined by a flame photometer (Instrumentation Laboratories), and creatinine was measured with an autoanalyzer (Technicon Corp). For measurement of the stable end products of NO (NO₂ and NO₃), samples were first incubated with Escherichia coli nitrate reductase to convert NO₃ to NO₂, as described by Bartholomew⁴² and Granger et al.⁴³ For preparation of this enzyme, Escherichia coli (American Type Culture Collection 25922) was grown for 18 hours under anaerobic conditions, washed, resuspended in phosphate-buffered saline, and frozen at -70°C until use. The samples were incubated with the enzyme in a ratio of 50:1 (sample/enzyme) in HEPES/ammonium formate buffer for 1 hour at 37°C. In preliminary assays, this ratio and time were found to give maximum and virtually complete reduction of NO₃, without any significant effect on NO₂ levels of standards or of samples. After the enzyme incubation, the total NO₂ in the samples (representing both NO₂ and the reduced NO₃) was measured with the Griess reagent, as previously described.^{44 45} Known concentrations of NaNO₂ and NaNO₃ were used as standards in each assay. One of the present researchers (L.R.) has already used this technique successfully in the laboratory to measure changes in serum NOx in rats.^{46 47}

Blood for ANP determination was collected in iced tubes containing 1.5 mg EDTA and 1 trypsin inhibitor unit of aprotinin. Plasma was separated by centrifugation at 4°C. Plasma samples were stored at -80°C until assay. Plasma ANP concentration was measured by a modification of the method of Tanaka et al⁴⁸ and Eskay et al.⁴⁹ Plasma for ANP determination was extracted with Sep-Pak C18 cartridges (Waters Associates). Extracts were dried under vacuum and reconstituted in radioimmunoassay buffer. Rat ANP-(1-28) (Peninsula Laboratories) was used as the reference standard. Rabbit anti–rat ANP-(99-126) antiserum was generously donated by Wyeth Laboratories. During the assay, 10 µL standard (2 to 250 pg) or sample was incubated for 48 hours at 4°C with 100 µL (8000 cpm) ¹²⁵I-labeled rat ANP (DuPont–New England Nuclear Research Products), 100 µL ANP antiserum, and 200 µL radioimmunoassay buffer (50 mmol/L potassium phosphate buffer, pH 7.4, containing 0.1% Triton X-100, 50 µmol/L phenylmethylsulfonyl fluoride, 50 mmol/L NaCl, and 0.0005% aprotinin). Separation of bound from free tracer was done by addition of 750 µL of 20% polyethylene glycol 8000 and 75 µL of 1.5% bovine -globulin to each assay tube and centrifugation for 1 hour at 2200g. Recovery of ANP from plasma, as assessed by addition of unlabeled ANP-(8-33) to normal rat plasma, was 91±4%. Nonspecific binding of the tracer was 3%. The sensitivity of the ANP radioimmunoassay was 3.3 pg per assay tube, with 50% displacement at 33 pg per assay tube.

Statistical analysis of the data was performed by ANOVA for comparison between means and by Fisher's exact test for multiple comparisons. Relationships between parameters were assessed by linear regression analysis. Data are expressed as mean±SE.

	Results

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The results of blacks are detailed in Table 1. Hypertensive patients were older than control subjects, but the difference in age did not reach statistical significance. Salt-sensitive and salt-resistant patients had similar ages. Under conditions of low Na⁺ intake, MAP levels in salt-sensitive patients (99±3.5 mm Hg) were similar to those of salt-resistant patients (98±2.3 mm Hg). Under condition of high Na⁺ intake, MAP levels were significantly greater (P<.01) in salt-sensitive (111±4.3 mm Hg) than in salt-resistant (97±2.3 mm Hg) patients. During high NaCl intake, salt-sensitive patients displayed a positive Na⁺ balance of 441±48 mEq and gained 1.4±0.5 kg body weight. Salt-resistant patients had a positive Na⁺ balance of 360±54 mEq and gained 1.1±0.19 kg body weight, whereas normotensive subjects had a positive Na⁺ balance of 242±67 mEq (P<.05 versus salt-sensitive patients) and gained 0.88±0.52 kg body weight. We cannot explain the discrepancy between Na⁺ balance and body weight gain, unless patients had substantial losses of Na⁺ with feces or unless they were in negative caloric balance.

The results of white patients are detailed in Table 2. Salt-sensitive and salt-resistant patients were matched for age and sex. Under conditions of low Na⁺ intake, MAP levels in salt-sensitive patients (109±3.1 mm Hg) were similar to those of salt-resistant patients (111±2.6 mm Hg). Under conditions of high Na⁺ intake, MAP levels were significantly greater (P<.01) in salt-sensitive (122±4.3 mm Hg) than salt-resistant (112±2.7 mm Hg) patients.

Under conditions of low Na⁺ intake, plasma ANP levels in blacks did not differ between salt-sensitive (38.5±11.9 pg/mL) and salt-resistant (53±11.9 pg/mL) patients with hypertension and control subjects (35.6±12.6 pg/mL). Under conditions of high Na⁺ intake, plasma ANP levels did not change in control subjects and salt-resistant patients (39±16.7 and 55±13.8 pg/mL, respectively) but decreased in salt-sensitive black patients (20.5±6.9 pg/mL, P<.05). Under conditions of high Na⁺ intake, plasma ANP levels were significantly greater (P<.01) in salt-resistant than in salt-sensitive blacks (Fig 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. Plasma ANP levels in salt-sensitive and salt-resistant black patients with essential hypertension under conditions of low (20 mmol/d) and high (250 mmol/d) dietary sodium intake. *P<.01 compared with low sodium intake; #P<.05 compared with salt-sensitive patients.

Under conditions of low Na⁺ intake, plasma ANP levels were higher in salt-sensitive (73±13.2 pg/mL) than in salt-resistant (32±11.5 pg/mL) white patients. Under conditions of high Na⁺ intake, plasma ANP levels did not change in salt-resistant white patients (40±7.7 pg/mL) and tended to decrease in salt-sensitive patients (50±12.1 pg/mL), but the difference did not reach statistical significance. Under conditions of high Na⁺ intake, plasma ANP levels were not different between salt-resistant and salt-sensitive hypertensive whites (Fig 2).

View larger version (29K): [in this window] [in a new window]   Figure 2. Plasma ANP levels in salt-sensitive and salt-resistant white patients with essential hypertension under conditions of low (20 mmol/d) and high (250 mmol/d) dietary sodium intake.

Under conditions of low dietary Na⁺ intake, plasma NO_x levels were higher (P<.05) in salt-sensitive (189±7.9 µmol/L) and salt-resistant (195±13.5 µmol/L) black patients than in control subjects (108±9.7 µmol/L). With high Na⁺ intake, plasma NO_x decreased significantly (P<.01) in both salt-sensitive (150±7.0 µmol/L) and salt-resistant (142±9.0 µmol/L) black patients. In normotensive black subjects, plasma NO_x decreased from 108±9.7 to 95±13.9 µmol/L, but the difference did not reach statistical significance (Fig 3). NO_x was not measured in white patients.

View larger version (32K): [in this window] [in a new window]   Figure 3. Plasma levels of NO2+NO3 in salt-sensitive and salt-resistant black patients with essential hypertension and in normotensive subjects under conditions of low (20 mmol/d) and high (250 mmol/d) dietary sodium intake. *P<.01 vs low sodium intake; #P<.05 vs controls.

	Discussion

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This study has demonstrated that salt-sensitive hypertensive blacks manifest abnormal ANP secretion in response to increased dietary Na⁺ intake. Salt-resistant patients failed to manifest the expected rise in ANP, whereas salt-sensitive patients manifested a paradoxical decrease in ANP. In these patients, reduced atrial secretion of ANP could be at least partly responsible for the reduced ability to excrete Na⁺ and for the Na⁺-induced rise in blood pressure. In whites, we noticed a similar tendency for ANP to decrease during high salt intake, but the decrease did not reach statistical significance.

Previous measurements of plasma ANP levels in patients with essential hypertension have provided conflicting results. Some studies have shown low to normal plasma ANP levels,^{50 51 52} whereas others have shown increased levels.^{53 54 55} Sagnella et al⁵⁶ showed an increase in plasma ANP levels during high Na⁺ intake in patients with essential hypertension. Kohno et al⁵⁷ showed that Na⁺ loading increased plasma ANP more in salt-sensitive than salt-resistant patients. Nimura,⁵⁸ on the other hand, showed a blunted increase in plasma ANP in response to high dietary NaCl intake in salt-sensitive compared with salt-resistant patients. Ferrari et al⁵⁹ and Weidmann et al⁶⁰ observed markedly reduced plasma ANP during high sodium intake in offspring of hypertensive parents compared with offspring of normotensive parents. They suggested that a relative ANP deficiency may potentially predispose individuals to the development of essential hypertension. These latter observations are in accordance with the current findings. The discrepancy in ANP findings in the literature could be partly due to methodological discrepancies in ANP measurements, to differences in age and dietary NaCl intake, to the presence of left ventricular dysfunction, or to genetic differences of the populations studied.

Studies in rats also showed increased ANP levels in response to NaCl loading in Wistar-Kyoto but not in NaCl-sensitive spontaneously hypertensive rats.⁶¹ ANP infusion in a dose that achieves plasma ANP levels well within the physiological range abolished the NaCl-induced exacerbation of hypertension in salt-sensitive spontaneously hypertensive rats.⁶² ANP secretion in response to increased atrial pressure was impaired in prehypertensive Dahl salt-sensitive rats but was exaggerated in more advanced phases when hypertension was complicated by left ventricular hypertrophy.⁶³

The current study has also shown that under conditions of low NaCl intake, hypertensive blacks manifest an increase rather than a decrease in plasma NO_x. This increase may represent an attempt of vasodilator substances to counteract the pressor effect of increased blood levels of vasoconstrictors, such as norepinephrine and angiotensin II, which occur in response to dietary NaCl restriction.⁶⁴ NO production is regulated not only by changes in flow and sheer stress but also by changes in vasoconstrictor stimuli.^{65 66 67} Previous studies have shown impaired vasodilator responses to either acetylcholine or methacholine in the forearm of patients with essential hypertension.^{32 33 34} However, in another study, vasodilator responses to nitroprusside and carbachol were similar in hypertensive and normotensive individuals.³⁷ Inhibition of NO synthase has provided evidence that basal NO-mediated vasodilatation is deficient in patients with hypertension.^{30 68} The reasons for these discrepancies are not clear. Studies have suggested that in certain models, NO synthesis may be increased but masked by the increased vasoconstrictor reactivity of the underlying vascular smooth muscle.²⁹ If this is the case, it is conceivable that for as long as the endothelium is functionally intact, NO synthesis in hypertension may be upregulated. However, once the endothelium is dysfunctional, NO synthesis may decrease and peripheral vascular resistance, the hallmark of hypertension, may increase further. Thus, assessment of NO production in hypertension will depend highly on the status of the endothelium, the vascular smooth muscle cells, and whether there is concomitant production of endothelium-derived contracting factors. In addition, the results obtained may differ depending on whether the techniques used assess primarily basal or stimulated NO synthesis. Physical exercise increases vascular NO production in experimental animals,⁶⁹ and basal levels of NO₂ are increased in marathon runners.⁷⁰

High dietary salt intake reduced serum NOx in both normotensive and hypertensive individuals independently of their blood pressure response to changes in dietary NaCl intake. One could speculate that the reduction in NOx levels during high dietary NaCl intake is a physiological response to decreased secretion of pressor hormones, such as norepinephrine and angiotensin II.⁶⁴ Alternatively, the inhibition of NO production could be responsible for the decrease in peripheral sympathetic nerve activity.⁷¹ Finally, high NaCl intake may have some as yet unknown effects on vascular endothelial cells leading to suppression of NO production. In salt-resistant Dahl/Rapp rats, ingestion of high NaCl diet impairs the myogenic response of renal afferent arterioles³⁷ and the dilation of large cerebral collateral arterioles in response to cerebral occlusion,³⁸ two hemodynamic responses thought to be endothelium dependent. In addition, high dietary NaCl intake attenuates the flow-dependent arteriolar dilation in rat spinotrapezius muscle, an action partly mediated by the action of endogenous NO.³⁹ These studies suggest that high NaCl intake suppresses NO activity in the peripheral resistance vessels. An exception could be the rat renal vasculature. In fact, 2 to 3 weeks of high NaCl intake presumably lead to increased NO production in the rat renal vasculature and a subsequent increase in glomerular filtration rate and sodium excretion.³⁵

In conclusion, the current studies have demonstrated that under conditions of high salt intake, salt-sensitive black patients manifest a deficiency in ANP secretion. This abnormality could play a role in the reduced ability of these patients to excrete an Na⁺ load and in the Na⁺-induced rise in blood pressure. Salt-sensitive patients, however, do not display abnormal NOx plasma levels, but high NaCl intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

	Acknowledgments

 
This work was supported in part by National Institutes of Health (NIH) grants R01 HL-47881 and HL-47081 and NIH National Center for Research Resources, General Clinical Research Center grant M01 RR-43.

Received November 30, 1995; first decision December 26, 1995; accepted April 29, 1996.

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