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Circulating atrial natriuretic peptides in hyperthyroidism and hypothyroidism
Circulating Atrial Natriuretic Peptides in Hyperthyroidism and Hypothyroidism
MASAKAZU KOHNO, M.D. KOH-ICHI MURAKAWA, M.D. KENICHI YASUNARI, M.D. YOSHIHIKO NISHIZAWA, M.D. HIROTOSHI MORII, M.D. TADANAO TAKEDA, M.D.
Plasma concentrations of atrial natriuretic peptides were measured in 32 normal control subjects, 25 patients with hyperthyroidism, and 18 patients with hypothyroidism. Atrial natriuretic peptide values were measured before and after successful therapy with methimazole or lthyroxine. Plasma atrial natriuretic peptide concentration was increased in patients with hyperthyroidlsm (48.0 f 19.5 pg/ml) but was decreased in patients with severe hypothyroidism (18.3 f 5.7 pg/ml) compared with values in normal control subjects (3 1.2 f 9.5 pg/ml). There was no significant difference between values in normal control subjects and mildly hypothyroid patients (35.0 f 12.2 pg/ml). The plasma atrlal natriuretic peptide concentration was correlated with the serum thyroxine level and heart rate. The elevated atrial natriuretic peptide concentration in hyperthyroidism decreased, whereas the reduced atrial natriuretic peptide concentration in severe hypothyroidism increased, compared with the initial value after successful therapy. These results suggest that plasma atrial natriuretic peptide concentration is frequently increased in hyperthyroidism and is frequently decreased in severe hypothyroidism, and that thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides.
Osaka, Japan
Mammalian cardiac atria contain biologically active peptides that are capable of producing diuresis, natriuresis, and vasodilation [I-S]. These atrial natriuretic peptides probably intervene in the control of water and sodium balance as well as blood pressure [6-lo]. On the other hand, thyroid dysfunction is known to be associated with alterations in renal function, the cardiovascular system, and total body water [ 1 I]. Recently, we [ 121 and Ladenson et al [ 131 showed that the plasma atrial natriuretic peptide concentration was increased in experimental hyperthyroid rats and was decreased in hypothyroid rats. In the current study, we measured plasma atrial natriuretic peptide concentrations in patients with hypetthyroidism and hypothyroidism, and examined the relationship between plasma atrial natriuretic peptide concentration and thyroid hormone concentration. PATIENTS AND METHODS From the First and Second Departments of Internal Medicine, Osaka City University Medical School, Abeno-ku, Osaka, Japan. Requests for reprints should be addressed to Dr. Masakazu Kohno, First Department of Internal Medicine, Osaka City University Medical School, l-5-7, Asahi-machi, Abeno-ku, Osaka 545, Japan. Manuscript submitted February 10, 1987, and accepted May 7, 1987.
646
October
1967
The American
Journal
Plasma atrial natriuretic peptide concentrations were measured in 25 patients with hyperthyroidism (five male and 20 female patients aged 15 to. 62 years) and in 18 patients with hypothyroidism (four male and 14 female patients aged 32 to 68 years). The diagnosis of hyperthyroidism and hypothyroidism was confirmed by thyroid function tests. Hypothyroidism was classified according to the serum thyroxine level into mild hypothyroidism (serum thyroxine level: 2 pg/dl to 4 pg/dl) and severe hypothyroidism (serum thyroxine level: 1 pg/dl to 2 pg/dl). In 12 patients with hyperthyroid-
of Medicine
Volume
63
ANP
ism, the change in plasma atrial natriuretic peptide concentration was followed during methimazole (methylmercaptoimidazole) therapy. In six patients with severe hypothyroidism, the change was monitored during i-thyroxine (sodium l-thyroxine) therapy. Patients treated with diuretics or antihypertensive drugs were excluded from the study, since these drugs have an effect on the release of atrial natriuretic peptides [6]. Patients with congestive heart failure were also excluded. Thirty-two normotensive healthy subjects served as controls (11 male and 21 female subjects aged 23 to 62 years). All examinations were carried out in the morning. After blood pressure and heart rate were measured, peripheral venous blood samples were collected from the patients while in the supine position for five minutes Blood for the measurement of atrial natriuretic peptides was drawn immediately into ice-chilled siliconized disposable tubes containing Trasylol (500 K.I.U./ml) and EDTA (1 mg/ml). Plasma was separated by centrifugation for IO minutes at 4OC and immediately frozen and stored at -8OOC for several days. The plasma atrial natriuretic peptide concentration was measured according to the method previously reported [6,9,14]. The serum thyroxine concentration was determined by radioimmunoassay. The statistical significance of the results was evaluated by an analysis of variance, and p values were determined by Duncan’s test. The correlations among plasma atrial natriuretic peptide concentration and serum thyroxine concentration, heart rate, and blood pressure level were analyzed by linear regression analysis. The comparisons between the values before and after therapy were analyzed by paired analysis of variances and were re-examined by Greenhouse and Geissor’s [15] method. Values were expressed as mean f SD. RESULTS Plasma concentrations of atrial natriuretic peptides in patients with hyperthyroidism, mild hypothyroidism, and severe hypothyroidism were 48.0 f 19.5 pg/ml, 35.0 f 12.2 pg/ml, and 16.3 f 5.7 pg/ml, respectively. The atrial natriuretic peptide value in 32 normotensive control subjects was 3 1.2 f 9.5 pg/ml. The plasma concentration of atrial natriuretic peptides was significantly increased in patients with hypetthyroidism and was significantly decreased in patients with severe hypothyroidism, compared with values in normal control subjects and mildly hypothyroid patients (Figure IA). There was no significant difference between values in normal control subjects and mildly hypothyroid patients. The plasma atrial natriuretic peptide concentration was correlated with the serum thyroxine concentration in hyperthyroidism (n = 25, r = 0.62, p
October
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
ET AL
serum thyroxine concentrations before and after successful therapy with methimazole (dosage, IO mg per day to 40 mg per day; duration, four weeks to 16 weeks) in the 12 patients with hyperthyroidism that were monitored. The plasma atrial natriuretic peptide concentration decreased (p (0.05) from the initial value of 55.3 f 22.2 pg/ml to the baseline value of 37.8 f 9.9 pg/ml as the thyroid hormone concentration returned to the euthyroid level. Figure 28 shows plasma atrial natriuretic peptide concentrations and serum thyroxine concentrations before and after successful therapy with l-thyroxine (dosage, 100 pg per day to 250 yg per day; duration, eight weeks to 12 weeks) in six patients with severe hypothyroidism. The plasma atrial natriuretic peptide concentration increased (p
1987
The American
Journal
of Medicine
Volume
83
649
ANP
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
p-co.01
I
A
ET AL
I
p
I
p
1
p-co.01
l
:
2
A
0
l A
--
-
--
A
-f
-
& A
0 0”
-H-
-2em
-
0 0 0
- t
---;I.-
A
-- 8
I
I
Controls
I
Hyperthyroidism
I
Mild
Severe hwthyroidism
hypothyroidism
120 -
B
n= 25 r=0.62
100 -
P-CO.01
40
80 l
l
le
60 -
l
l
l
30
l l
l
20 ee
l
l e
/
‘8
0
10
l
rz0.63
0
P-CO.01
“a
1
(
14
18
22
26
0
1
Serum T4 (pg/de)
3 2 Serum T4 (,ugldQ)
4
Figure 1. A, plasma concentration of atrial natriuretic peptides in normal co* trol subjects and patients with hyperthyroid&m, mild hypothyroidism, or severe hypothyroidism. Correlation between the plasma concentration of atrial natriuretic peptides and the serum thyroxine concentration in patients with hyperthyroi& ism (s) and hypothyroidism (C).
mone is associated with the release of atrial natriuretic peptides from the atrium. This hypothesis is supported by the finding that the elevated plasma atrial natriuretic peptide concentration in hyperthyroidism decreased and the reduced plasma atrial natriuretic peptide concentration in severe hypothyroidism increased along with the normalization in the serum thyroid hormone concentration. However, both release and synthesis of atrial natriuretic peptides might be increased in hyperthyroid patients, since Gardner et al [ 171 demonstrated that thyroxine increased the release of atrial natriuretic peptide and mRNA for atrial
natriuretic peptide in cultured neonatal rat cardiocytes. We also cannot exclude the possibility that the synthesis of atrial natriuretic peptides is decreased in severe hypothyroidism, since the synthesis of protein and lipid is known to be decreased in this disorder. Another possible mechanism is the influence of secondary hemodynamic changes, accompanied by thyroid dysfunction, on the release of atrial natriuretic peptide. Tachycardia is frequently observed in hyperthyroidism, and bradycardia is frequently observed in hypothyroidism. An increased plasma concentration of atrial natriuretic peptides is reported in paroxysmal supraventricular tachy-
650
63
tions are consistent with the hypothesis that thyroid hor-
October
1967
The American
Journal
of Medicine
Volume
ANP
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
ET AL
s F .E 100 5 .-c, F! g 60? $
40-
2
2 a
Figure 2. Changes in the plasma atria/ natriuretic peptide concentration and serum thyroxine concentration after SW cessful therapy in patients with hyperthyroidism (A) and severe hypothyroid ism (B).
20-
0
1
Serum T4 20.2 (/.ig/dL?) AI 3.5
cardia [ 181 and tachycardia induced by atrial pacing [ 191 and dynamic exercise [ 141. The current study also showed a significant correlation between plasma atrial natriuretic peptide concentration and heart rate. Tachycardia or bradycardia secondary to thyroid dysfunction might be, in part, associated with altered levels of plasma atrial natriuretic peptide. Cardiac output is decreased because of a reduction of heart rate and stroke volume in hypothyroidism [ 1 I]. Plasma atrial natriuretic peptide concentration is found to be high in congestive heart failure [20,21]. However, the plasma concentration of atrial natriuretic peptides in severely hypothyroid patients in this study was decreased compared with that in normal control subjects. This finding suggests that the release of atrial natriuretic peptides in severe hypothyroidism may be, at least in part, regulat-
** P
*p
1.6 kO.1
7.9 iL2.1
ed by factors other than secondary changes in cardiac hemodynamics. However, we could not determine whether the effect of thyroid hormone on the plasma atrial natriuretic peptide concentration is primary, secondary, or both. Although the precise mechanism involved in the alterations of plasma atrial natriuretic peptide concentrations in different thyroid states remains to be clarified, our data suggest that the thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides. ACKNOWLEDGMENT We thank Dr. T. Inoue, associate professor of medicine, for help in the statistical review and Miss M. Kishi for technical assistance.
REFERENCES 1.
2.
de Bold AJ, Borenstein HB, Veress AT, et al: A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28: 89-94. Kangawa K, Matuo H: Purification and complete amino acid sequence of a-human atrial natriuretic polypeptide ((YhANP). Biochem Biophys Res Commun 1984; 118: i31139.
October
3.
4.
5.
1987
Atlas SA, Kleinert HD, Camargo MJ, et al: Purification, sequencing and synthesis of natriuretic and vasoactive rat atrial peptide. Nature 1984; 309: 717-719. Currie MG, Geller DM, Cole RR, et al: Purification and sequence analysis of bioactive atrial peptides (atriopeptins). Science 1984; 223: 67-69. Kleinert HD, Maack T, Atlas SA, et al: Atrial natriuretic factor
The American
Journal
of Medicine
Volume
83
851
ANP IN HYPERTHYROIDISM
10.
11. 12.
13.
652
AND HYPOTHYROIDISM-KOHNO
ET AL
inhibits antiotensin, norepinephrine, and potassium-induced vascular contractility. Hypertension 1984; 6 (suppl 1): 143-147. Kohno M, Yasunari K, Murakawa K, et al: Circulating atrial natriuretic polypeptide in essential hypertension. Am Heart J 1987; 113: 1160-l 163. Sagnella GA, MacGregor GA: Cardiac peptides and the control of sodium excretion. Nature 1984; 309: 666-667. Lang RE, Tholken H, Ganten D, et al: Atrial natriuretic factor-a circulating hormone stimulated by volume loading. Nature 1985; 314: 264-266. Kohno M, Sambhi MP, Eggena P, et al: An accelerated increase of circulating atrial natriuretic polypeptide in salt-loaded spontaneously hypertensive rats. Horm Metab Res 1986; 18: 147-148. Kohno M, Yasunari K, Murakawa K, et al: Effects ofhighsodium and low-sodium intakes on circulating atrial natriuretic peptides in salt-sensitive patients with systemic hypertension. Am J Cardiol 1987; 59: 1212-1213. lngbar SH, Woeber KA: Textbook of endocrinology. Philadelphia: WB Saunders, 1974; 157-162, 191-199. Kohno M, Takaori K, Matsuura T, et al: Atrial natriuretic polypeptide in atria and plasma in experimental hyperthyroidism and hypothyroidism. Biochem Biophys Res Commun 1986; 134: 178-183. Ladenson PW, Michener M, Langevin H, et al: Plasma and atrial atriopeptin concentrations in hyperthyroid, euthyroid, and hypothyroid rats. In: Proceedings of the 68th
October
1967
The American
Journal
of Medicine
Volume
14.
1.5. 16.
17.
18.
19.
20.
21.
63
Annual Meeting of the Endocrine Soceity, Anaheim, California, 1986, 235. Nishikimi T, Kohno M, Matsuura T, et al: Effect of exercise on circulating atrial natriuretic polypeptide in valvular heart disease. Am J Cardiol 1986; 58: 1119-l 120. Greenhouse SW, Geissor S: On methods in the analysis of profile data. Psychometrika 1954; 24: 95-l 12. Zimmerman RS, Gharib H, Zimmerman D, et al: Atrial natriuretic peptide in hypothyroidism. J Clin Endocrinol Metab 1987; 64: 353-355. Gardner DG, Horne S, Gertz BJ, et al: Expression of the gene for atrial natriuretic factor is regulated by thyroid hormone. In: Proceedings of the 68th Annual Meeting of the Endocrine Society, Anaheim, California, 1986, 60. Schiffrin EL, Gutkowaska J, Kuchel 0, et al: Plasma concentration of atrial natriuretic factor in a patient with paroxysmal atrial tachycardia (letter). N Engl J Med 1985; 312: 1196. Gutkowaska J, Bourassa M, Roy G, et al: lmmunoreactive atrial natriuretic factor (IR-ANF) in human plasma. Biothem Biophys Res Commun 1985; 128: 1350-1357. Tikkanen I, Fyhrquit F, Metsarinne K, et al: Plasma atrial natriuretic peptide in cardiac disease and during infusion in healthy volunteers. Lancet 1985; II: 66-69. Tsunoda K, Hodsman GP, Smithman E, et al: Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction. Circ Res 1986; 59: 256261.
MASAKAZU KOHNO, M.D. KOH-ICHI MURAKAWA, M.D. KENICHI YASUNARI, M.D. YOSHIHIKO NISHIZAWA, M.D. HIROTOSHI MORII, M.D. TADANAO TAKEDA, M.D.
Plasma concentrations of atrial natriuretic peptides were measured in 32 normal control subjects, 25 patients with hyperthyroidism, and 18 patients with hypothyroidism. Atrial natriuretic peptide values were measured before and after successful therapy with methimazole or lthyroxine. Plasma atrial natriuretic peptide concentration was increased in patients with hyperthyroidlsm (48.0 f 19.5 pg/ml) but was decreased in patients with severe hypothyroidism (18.3 f 5.7 pg/ml) compared with values in normal control subjects (3 1.2 f 9.5 pg/ml). There was no significant difference between values in normal control subjects and mildly hypothyroid patients (35.0 f 12.2 pg/ml). The plasma atrlal natriuretic peptide concentration was correlated with the serum thyroxine level and heart rate. The elevated atrial natriuretic peptide concentration in hyperthyroidism decreased, whereas the reduced atrial natriuretic peptide concentration in severe hypothyroidism increased, compared with the initial value after successful therapy. These results suggest that plasma atrial natriuretic peptide concentration is frequently increased in hyperthyroidism and is frequently decreased in severe hypothyroidism, and that thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides.
Osaka, Japan
Mammalian cardiac atria contain biologically active peptides that are capable of producing diuresis, natriuresis, and vasodilation [I-S]. These atrial natriuretic peptides probably intervene in the control of water and sodium balance as well as blood pressure [6-lo]. On the other hand, thyroid dysfunction is known to be associated with alterations in renal function, the cardiovascular system, and total body water [ 1 I]. Recently, we [ 121 and Ladenson et al [ 131 showed that the plasma atrial natriuretic peptide concentration was increased in experimental hyperthyroid rats and was decreased in hypothyroid rats. In the current study, we measured plasma atrial natriuretic peptide concentrations in patients with hypetthyroidism and hypothyroidism, and examined the relationship between plasma atrial natriuretic peptide concentration and thyroid hormone concentration. PATIENTS AND METHODS From the First and Second Departments of Internal Medicine, Osaka City University Medical School, Abeno-ku, Osaka, Japan. Requests for reprints should be addressed to Dr. Masakazu Kohno, First Department of Internal Medicine, Osaka City University Medical School, l-5-7, Asahi-machi, Abeno-ku, Osaka 545, Japan. Manuscript submitted February 10, 1987, and accepted May 7, 1987.
646
October
1967
The American
Journal
Plasma atrial natriuretic peptide concentrations were measured in 25 patients with hyperthyroidism (five male and 20 female patients aged 15 to. 62 years) and in 18 patients with hypothyroidism (four male and 14 female patients aged 32 to 68 years). The diagnosis of hyperthyroidism and hypothyroidism was confirmed by thyroid function tests. Hypothyroidism was classified according to the serum thyroxine level into mild hypothyroidism (serum thyroxine level: 2 pg/dl to 4 pg/dl) and severe hypothyroidism (serum thyroxine level: 1 pg/dl to 2 pg/dl). In 12 patients with hyperthyroid-
of Medicine
Volume
63
ANP
ism, the change in plasma atrial natriuretic peptide concentration was followed during methimazole (methylmercaptoimidazole) therapy. In six patients with severe hypothyroidism, the change was monitored during i-thyroxine (sodium l-thyroxine) therapy. Patients treated with diuretics or antihypertensive drugs were excluded from the study, since these drugs have an effect on the release of atrial natriuretic peptides [6]. Patients with congestive heart failure were also excluded. Thirty-two normotensive healthy subjects served as controls (11 male and 21 female subjects aged 23 to 62 years). All examinations were carried out in the morning. After blood pressure and heart rate were measured, peripheral venous blood samples were collected from the patients while in the supine position for five minutes Blood for the measurement of atrial natriuretic peptides was drawn immediately into ice-chilled siliconized disposable tubes containing Trasylol (500 K.I.U./ml) and EDTA (1 mg/ml). Plasma was separated by centrifugation for IO minutes at 4OC and immediately frozen and stored at -8OOC for several days. The plasma atrial natriuretic peptide concentration was measured according to the method previously reported [6,9,14]. The serum thyroxine concentration was determined by radioimmunoassay. The statistical significance of the results was evaluated by an analysis of variance, and p values were determined by Duncan’s test. The correlations among plasma atrial natriuretic peptide concentration and serum thyroxine concentration, heart rate, and blood pressure level were analyzed by linear regression analysis. The comparisons between the values before and after therapy were analyzed by paired analysis of variances and were re-examined by Greenhouse and Geissor’s [15] method. Values were expressed as mean f SD. RESULTS Plasma concentrations of atrial natriuretic peptides in patients with hyperthyroidism, mild hypothyroidism, and severe hypothyroidism were 48.0 f 19.5 pg/ml, 35.0 f 12.2 pg/ml, and 16.3 f 5.7 pg/ml, respectively. The atrial natriuretic peptide value in 32 normotensive control subjects was 3 1.2 f 9.5 pg/ml. The plasma concentration of atrial natriuretic peptides was significantly increased in patients with hypetthyroidism and was significantly decreased in patients with severe hypothyroidism, compared with values in normal control subjects and mildly hypothyroid patients (Figure IA). There was no significant difference between values in normal control subjects and mildly hypothyroid patients. The plasma atrial natriuretic peptide concentration was correlated with the serum thyroxine concentration in hyperthyroidism (n = 25, r = 0.62, p
October
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
ET AL
serum thyroxine concentrations before and after successful therapy with methimazole (dosage, IO mg per day to 40 mg per day; duration, four weeks to 16 weeks) in the 12 patients with hyperthyroidism that were monitored. The plasma atrial natriuretic peptide concentration decreased (p (0.05) from the initial value of 55.3 f 22.2 pg/ml to the baseline value of 37.8 f 9.9 pg/ml as the thyroid hormone concentration returned to the euthyroid level. Figure 28 shows plasma atrial natriuretic peptide concentrations and serum thyroxine concentrations before and after successful therapy with l-thyroxine (dosage, 100 pg per day to 250 yg per day; duration, eight weeks to 12 weeks) in six patients with severe hypothyroidism. The plasma atrial natriuretic peptide concentration increased (p
1987
The American
Journal
of Medicine
Volume
83
649
ANP
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
p-co.01
I
A
ET AL
I
p
I
p
1
p-co.01
l
:
2
A
0
l A
--
-
--
A
-f
-
& A
0 0”
-H-
-2em
-
0 0 0
- t
---;I.-
A
-- 8
I
I
Controls
I
Hyperthyroidism
I
Mild
Severe hwthyroidism
hypothyroidism
120 -
B
n= 25 r=0.62
100 -
P-CO.01
40
80 l
l
le
60 -
l
l
l
30
l l
l
20 ee
l
l e
/
‘8
0
10
l
rz0.63
0
P-CO.01
“a
1
(
14
18
22
26
0
1
Serum T4 (pg/de)
3 2 Serum T4 (,ugldQ)
4
Figure 1. A, plasma concentration of atrial natriuretic peptides in normal co* trol subjects and patients with hyperthyroid&m, mild hypothyroidism, or severe hypothyroidism. Correlation between the plasma concentration of atrial natriuretic peptides and the serum thyroxine concentration in patients with hyperthyroi& ism (s) and hypothyroidism (C).
mone is associated with the release of atrial natriuretic peptides from the atrium. This hypothesis is supported by the finding that the elevated plasma atrial natriuretic peptide concentration in hyperthyroidism decreased and the reduced plasma atrial natriuretic peptide concentration in severe hypothyroidism increased along with the normalization in the serum thyroid hormone concentration. However, both release and synthesis of atrial natriuretic peptides might be increased in hyperthyroid patients, since Gardner et al [ 171 demonstrated that thyroxine increased the release of atrial natriuretic peptide and mRNA for atrial
natriuretic peptide in cultured neonatal rat cardiocytes. We also cannot exclude the possibility that the synthesis of atrial natriuretic peptides is decreased in severe hypothyroidism, since the synthesis of protein and lipid is known to be decreased in this disorder. Another possible mechanism is the influence of secondary hemodynamic changes, accompanied by thyroid dysfunction, on the release of atrial natriuretic peptide. Tachycardia is frequently observed in hyperthyroidism, and bradycardia is frequently observed in hypothyroidism. An increased plasma concentration of atrial natriuretic peptides is reported in paroxysmal supraventricular tachy-
650
63
tions are consistent with the hypothesis that thyroid hor-
October
1967
The American
Journal
of Medicine
Volume
ANP
IN HYPERTHYROIDISM
AND
HYPOTHYROIDISM-KOHNO
ET AL
s F .E 100 5 .-c, F! g 60? $
40-
2
2 a
Figure 2. Changes in the plasma atria/ natriuretic peptide concentration and serum thyroxine concentration after SW cessful therapy in patients with hyperthyroidism (A) and severe hypothyroid ism (B).
20-
0
1
Serum T4 20.2 (/.ig/dL?) AI 3.5
cardia [ 181 and tachycardia induced by atrial pacing [ 191 and dynamic exercise [ 141. The current study also showed a significant correlation between plasma atrial natriuretic peptide concentration and heart rate. Tachycardia or bradycardia secondary to thyroid dysfunction might be, in part, associated with altered levels of plasma atrial natriuretic peptide. Cardiac output is decreased because of a reduction of heart rate and stroke volume in hypothyroidism [ 1 I]. Plasma atrial natriuretic peptide concentration is found to be high in congestive heart failure [20,21]. However, the plasma concentration of atrial natriuretic peptides in severely hypothyroid patients in this study was decreased compared with that in normal control subjects. This finding suggests that the release of atrial natriuretic peptides in severe hypothyroidism may be, at least in part, regulat-
** P
*p
1.6 kO.1
7.9 iL2.1
ed by factors other than secondary changes in cardiac hemodynamics. However, we could not determine whether the effect of thyroid hormone on the plasma atrial natriuretic peptide concentration is primary, secondary, or both. Although the precise mechanism involved in the alterations of plasma atrial natriuretic peptide concentrations in different thyroid states remains to be clarified, our data suggest that the thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides. ACKNOWLEDGMENT We thank Dr. T. Inoue, associate professor of medicine, for help in the statistical review and Miss M. Kishi for technical assistance.
REFERENCES 1.
2.
de Bold AJ, Borenstein HB, Veress AT, et al: A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28: 89-94. Kangawa K, Matuo H: Purification and complete amino acid sequence of a-human atrial natriuretic polypeptide ((YhANP). Biochem Biophys Res Commun 1984; 118: i31139.
October
3.
4.
5.
1987
Atlas SA, Kleinert HD, Camargo MJ, et al: Purification, sequencing and synthesis of natriuretic and vasoactive rat atrial peptide. Nature 1984; 309: 717-719. Currie MG, Geller DM, Cole RR, et al: Purification and sequence analysis of bioactive atrial peptides (atriopeptins). Science 1984; 223: 67-69. Kleinert HD, Maack T, Atlas SA, et al: Atrial natriuretic factor
The American
Journal
of Medicine
Volume
83
851
ANP IN HYPERTHYROIDISM
10.
11. 12.
13.
652
AND HYPOTHYROIDISM-KOHNO
ET AL
inhibits antiotensin, norepinephrine, and potassium-induced vascular contractility. Hypertension 1984; 6 (suppl 1): 143-147. Kohno M, Yasunari K, Murakawa K, et al: Circulating atrial natriuretic polypeptide in essential hypertension. Am Heart J 1987; 113: 1160-l 163. Sagnella GA, MacGregor GA: Cardiac peptides and the control of sodium excretion. Nature 1984; 309: 666-667. Lang RE, Tholken H, Ganten D, et al: Atrial natriuretic factor-a circulating hormone stimulated by volume loading. Nature 1985; 314: 264-266. Kohno M, Sambhi MP, Eggena P, et al: An accelerated increase of circulating atrial natriuretic polypeptide in salt-loaded spontaneously hypertensive rats. Horm Metab Res 1986; 18: 147-148. Kohno M, Yasunari K, Murakawa K, et al: Effects ofhighsodium and low-sodium intakes on circulating atrial natriuretic peptides in salt-sensitive patients with systemic hypertension. Am J Cardiol 1987; 59: 1212-1213. lngbar SH, Woeber KA: Textbook of endocrinology. Philadelphia: WB Saunders, 1974; 157-162, 191-199. Kohno M, Takaori K, Matsuura T, et al: Atrial natriuretic polypeptide in atria and plasma in experimental hyperthyroidism and hypothyroidism. Biochem Biophys Res Commun 1986; 134: 178-183. Ladenson PW, Michener M, Langevin H, et al: Plasma and atrial atriopeptin concentrations in hyperthyroid, euthyroid, and hypothyroid rats. In: Proceedings of the 68th
October
1967
The American
Journal
of Medicine
Volume
14.
1.5. 16.
17.
18.
19.
20.
21.
63
Annual Meeting of the Endocrine Soceity, Anaheim, California, 1986, 235. Nishikimi T, Kohno M, Matsuura T, et al: Effect of exercise on circulating atrial natriuretic polypeptide in valvular heart disease. Am J Cardiol 1986; 58: 1119-l 120. Greenhouse SW, Geissor S: On methods in the analysis of profile data. Psychometrika 1954; 24: 95-l 12. Zimmerman RS, Gharib H, Zimmerman D, et al: Atrial natriuretic peptide in hypothyroidism. J Clin Endocrinol Metab 1987; 64: 353-355. Gardner DG, Horne S, Gertz BJ, et al: Expression of the gene for atrial natriuretic factor is regulated by thyroid hormone. In: Proceedings of the 68th Annual Meeting of the Endocrine Society, Anaheim, California, 1986, 60. Schiffrin EL, Gutkowaska J, Kuchel 0, et al: Plasma concentration of atrial natriuretic factor in a patient with paroxysmal atrial tachycardia (letter). N Engl J Med 1985; 312: 1196. Gutkowaska J, Bourassa M, Roy G, et al: lmmunoreactive atrial natriuretic factor (IR-ANF) in human plasma. Biothem Biophys Res Commun 1985; 128: 1350-1357. Tikkanen I, Fyhrquit F, Metsarinne K, et al: Plasma atrial natriuretic peptide in cardiac disease and during infusion in healthy volunteers. Lancet 1985; II: 66-69. Tsunoda K, Hodsman GP, Smithman E, et al: Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction. Circ Res 1986; 59: 256261.