- Email: [email protected]
Decreased adrenergic sensitivity in patients with hypothyroidism
JACCVol. 15, No. I
94
January
I 94-S
ecre RALF POLIKAR,
MD, BRIAN KENNEDY,
,
PHD, ALAN
JOHANA SMITH, RN, HOWARD DITTRICH,
MD, FACC, PASCAL NICOD,
San Diego. California
Cardiovascularsensitivityto catecholamineswas assess4 in 15 patientswith hypothyroidism(mean [f SEMIthyroxine [Td] index 2.7 i 0.5 pg/loO ml, thyroid stimulating
hormone[TSH] 136.9 + .3 /.&J/ml),aged 45 f and ia 8 healthycontrolsubjects.The study was repeatedin 10 patients with hypothyroidism4.0 f 0.5 months after 2.1 #q/loo thyroid replacementtherapy (T4 index averageand mi, TSH3.5 f 1.3 @J/ml).In addition, maximalheart rates were measuredusing 24 h ambulatory electrocardiographic (KG) monitoring,and plasmalevels of ephrephrineand norepinephrinewere determinedbefore and after thyroid replacement. Heartrate increasedless afterbolus injectionof 0.8,1.6 and 3.2 jqgof isoprotereoolin the hypothyroid(10 f 2,15 P 2 and 21 i 4 beats/n@ respectively) than in tne
tively) state (p C
0.05).
ear&c cbroaotro muximaldaily heart rates seen in roidism, whichoccursdespite eleva rine levels.
euthyroid(16 f 3,22 i 3 and 30 I 4 beats/min,respec-
Patients with hypothyroidism often present with bradycardia, ptosis of the eyelids and other signs of low sympathetic activity (1). However, their plasma norepinephrine and epinephrine levels are high (2,3), suggesting decreased catecholamine sensitivity. The numerous studies (4-13) of beta-adrenergic responsiveness in various animal models of hypothyroidism have had conflicting results. Similarly, whether decreased sensitivity to beta-adrenergic stimulation is present in patients with hypothyroidism is still controversial (14-17). Therefore, this study assessed the heart rate response to beta-adrenergic stimulation of patients with hypothyroidism before and after thyroid replacement therapy.
From the Divisions of Cardiology and Nephrology. University of California-San Diego Medical Center and Veterans Administration Medical Center, San Diego, California. This study was supported in part by Grant HL 35924 and Clinical Research Center Grant MO1 RR 00827 from the National Institutes of Health, Bethesda, Maryland. Manuscript received March 20,198% revised manuscript received July 26, 1989, accepted August 8. 1989. Address for: Ralf Polikar, MD, Division of Cardiology, University of Cahfomia-San Diego Medical Center. 225 Dickinson Street, H-81 I-A, San Diego, California 92103. 01990 by the American College of Cardiology
Study patients. Fifteen patients (4 men and ii women), aged 27 to 76 years (mean f SEM 45 * 4), with newly diagnosed hypothyroidis.n were enrolled in this study from August 1987to June 1988.No patient had cardiac disease or was receiving drugs that might interact with cardiac or autonomic nervous system function. All medications, except thyroxine, remained unchanged throughout the protocol. All patients gave written informed consent to this medical center’s Httman Subjects Committee-approved protocol. Ten of the IS patients underwent both a baseline study in the hypothyroid state and a repeat study during thyroid replacement therapy with thyroxine 4 + 0.5 months after the baseline study. Five of the patients completed the baseline study, but refused to undergo a repeat study while in a euthyroid state. Eight healthy control subjects (three men and five women) with a mean age of 42 + 4 years and normal thyroid fu ts completed the same p All patients were admi search Center at 9:CWI AM in the morning and had an intravenous line inserted. Blood was drawn for thyroid function tests. Patients then rested supine for at least 2 h 073% 1097/901$3.50
JACC Vol. 15. MO. ! January I :94-s
ment well. Their mean weight of 83.7 t 7 kg at baseline
s were ana-
heart rate was automat~ca~~~ combated by using a 16 beat sliding average after checking for motion artifacts.
The isoproterenol infitsiun test gave reproducibleheart rates, with a variability between injections of 4 2 4 beats/
POLIKAR ET AL. HYPOTHYROIDISM AND SENSITIVITY
%
JAW Vol. 15. No. I January I 94-8
TO CATECHOLAMINES
Table 2. Decreases in Diastolic Blood Pressure (mm Hg) After Injection of Isoproterenol lsoproterenol 0.8 pg
patientswithhypothyroidism tn = 10) PaGentsin a hypolhyroid state (n = 7)*
All
Patients in a euthyroid state (n = 7)* Control subjects (n = 8)
1.6 j.~6
3.2 erg
2
13 f 2
16 i 4
422 IO + 2 12 + 2
14 f 3 20 f 5 22 2 4
20 + 5 31 r1 22 + 6
4 2
*Seven paGents studied before and abler replacement therapy.
therapy. Seven patients with hypothyroidism required 4.4 ccg and three required 12.8 clg of isoproterenol before thyroid replacement. After thyroid replacement, only two patients required 6.4 cogand none required 12.8 M. The increase in heart rate was also significantly lower w”lenall 15 patients with hypothyroidism were compared with the control subjects (Fig. 2). There was no significant correlation between the degree of hypothyroidism, assessed by T4 index and TSH levels, and the heart rate increase after injections of isoproterenol.
0-
WPO
Euth
Figure 1. Plasma levels of norepinephrine measured before (Hype) and after (Euth) thyroid replacement in IO patients with hypothy
roidism.
min (mean + SD). Patients reported minor side effects of palpitation (eight patients), deep sighing (eight patients), anxiety (five patients) and flushing (three patients). After injection of saline solution, the average increase in heart rate was 3 + 1 beat&n (mean k SEM). Injections of 0. I to 0.4 pg of isoproterenol resulted in only a minimal increase in heart rate in patients with hypothyroidism and control subjects (Fig. 2). After injection of 0.8, 1.6 and 3.2 H of isoproterenol, the increase in heart rate was significantly blunted in patients who had not yet received replacement
Baseline blood pressure measurements were similar in patients in the hypothyroid and the euthyroid state (125 rt 8/83 k 5 versus 127 2 7183 -I 6 mm Hg). Decreases in
diastolic blood pressure during isoproterenol infusion tended to be smaller in patients with hypothyroidism than in patients in the euthyroid state or in control subjects, although these differences did not reach statistical significance (Table 2). However, the changes in blood pressure during the
I-
40
NS
-I
30 20
Figure 2. lsoproterenol (ISO) sensitivity test results. A, Ten patients studied both before (Hype)
IS0 1.6 mcg
T 156 6.4 mcg 30
:
20 10 40
7
i
01
HYPO
Euth
r
P’O.05
-I
-l T I-P’O.05
All Hypo Controls IS0 6.4 mcg 30
:
20
-
10
:
: *
0 I_-
HYPO Euth
IS0 3 2 mcg
All
Hypo Controls
and after (Euth) thyroid replacement. B, Fifteen patients with hypothyroidism (All Hype) and eight control subjects (Controls).
JACC Vol. 15, No. 1 January 1 :94-8
asal, average and maxilrd
hean rates recorded du61g 24
We ‘dIdIlk Ana Hefty
for her experl assistance in the preparation of the Wrighl, MD. Boyle Park, MD and Steve Carter. BS for their he;p in the realization of this project. and Wolfgang ~i~~rna~n, MD for his guidance.
manuscripl. We thank Michael
rine levels and increased cardiac cbronotro~ic res~o~s~veroidism. Furthermonitoring. Thyroid replacement
I. Klein I. Levey GS. New perspectives on thyroid amines and the heart. Am J Med 1984;76: 167-72.
hormone,
catecbol-
2. Christensen NJ. Plasma noradrenaline and adrenaline in patients with thyrotoxicosis and myxoedema. Clin Sci Mol Med 1973;45:161-3.
increased heart rate response to adrenergic stimuiat~o~. e contribution of these two -mechanisms
3. Manhem P, Hallengren B, Nansson BG. Plasma noradrenaline and blood pressure in hypothyroid patients: effect of gradual thyroxine treatment. Clin Endocrinol 1984:20:701-7. 4.
Its. Admi~jstrat~on
3ilezikian JP. Loeb JN. The influence of bype~byroid~sm and hypotby,oidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Endocrinol Rev 1983:414:378-87.
5. Banerjee SP. Kung LS. Beta-adrenergic receptors in rat heart: effects of thyroideclomy. Eur J Pharmacol 1977:43:207-8.
occurs in euthyroid rats (8,12) and a smaller ~hronotro~~~ response to isoproterenol (9.13). These differences may be due to a decrease in the number of beta-adrenergic receptors (5). Studies performed in paiients with hypothyroidism also
6. McConnaughey MM. Jones LR, Watanabe AM. Bescb LT, Lefkowitz RI. Thyroxine and propylthiouracil effecls on alpha- :*nd beta-adrenergic receptor number, ATPase activities. and sialic acid content of rat cardiac membrane vesicles. J Cardiovasc Pharmacol 1979:1:609-23.
98
POLIKAR ET AL. I-IYPOTHYROIDISMAND SENSITIVITY TO CATECHOLAMINES
7. Stiles GL, L&owitz RJ. Thyroid hormone modulation of agonist betaadrecergic receptor interactions in the rat heart. Life Sci 1981;28:252936. 8. Ciaraldi TP, Marinetti GV. Hormone action at the membrane level. VII!. Adrenergic receptors in rat heart and adipocytes end their modulation by thyroxine. Biochem Biophys Acta 1978:541:334-46. 9. Kunos G, Mucci L, O’Regan S. The influence of hormonal and neuronal factors on rat heart adrenoreceptors. Br J Pharmacol 1980;71:371-86. 10. Noguchi A, Whitsett JA. Ontogeny of alpha,-adnnergic receptors in the rat myocardium: effects of hypothyroidism. Eur J Pharmacol 1983;86:4350. II. Williams RS, Lefkowitz RJ. The effect of thyroid hormone on adrenergic receptors. In: Oppenheimer JH. ed. Molecular Basis of Thyroid Hormone Action. London: Academic Press. 1983:325-49. 12. lshac BJN, Pennefather JN. Handberg GM. Effect of changes in thyroid state on atrial alpha- and beta-adrenoreceptors. adenylate cyclase activity, and catecholamine levels in the rat. J Cardiovasc Phanacol lY83:5: 3%-40X 13. Gross G, Lues 1. Thyroid-dependent alterations of myocardial adrenorecaptors and adrenoreceptor-mediated responses in the rat. Naunyn Schmiedebergs Arch Pharmacol 1985:329:427-39. 14. Harrison TS. Adrenal medullary and thyroid relationships. 1964;44:161-85. IS. Waldstein SS. Thyroid-catecholamine 17:123-33.
interrelations.
Pbysiol Rev
Ann Rev hied 1966;
16. Leak D, Lew M. Effect of treatmjent of hypothyroidism on circulatory response to adrenaline. Br Heart J 1%2;25:30-4. 17. McDevitt
ffi,
Riddell JG. Hadden
DR, Montgomery
DAD. Catechol-
JACC Vd. 15, No. I January 199tk94-8
amine sensitivity in hyperthyroidism and hypotbyroidism. Br 3 Clin Pharmacol 1978:6:297-301. 18. Cleaveland CR, Rangno RE. Shand DG. A standardized isoproterenol sensitivity test. Arch Intern Med 1972;130:47-52. 19. Chopra LJ, Solomon DH, Ho RS. A radioimmtinoassay of thyroxine. J Clin Endocrinol Metab 1971;33:865-8. 20. Stein RB, Price L. Evaluation of adjusted total thyroxine (free thyroxine
index) as a measure of thyroid function. J Clin P .ocrinol Metab 1972;34:225-8. 21. Larsen PR, Alexander NM, Chopra IJ, et al. Revised nomenclature for tests of thyroid hurmones and thyroid-related proteins in serum. J Clin Endocrinol Metab 1987:64:1089-92. 22. Ziegler MG, Woodson LC, Kennedy B. Radioenzymatic assay of catecholamines. metabolites and related e!?zymes. In: Krstulovic AR, ed. Quantitative Analysis of Catecholamines and Related Compounds. New York: John Wiley, 1986:263-80. 23. Polikar R, Feld GK. D&rich HC, Smith J, Nicod P. Effect of thyroid replacement therapy on the frequency of benign atrial and ventrl:ular arrhythmias. J Am Co8 Cardiol 1989;14:9YY-1002. 24. Freedberg AS. Papp JG, Vaughan Williams EM. The effect of altered thyroid state on atrial intracellular potentials. J Physiol 1970;207:357-69. 25. Maisel AS, Ziegler MG. Carter S, Insel PA. Motulsky HJ. In vivo regulation of Badrenergic receptors on mononuclear leukocytes and heart. J Clin Invest 1988;82:2038-44. 26. DeBlasi A, Maisel AS. Feldman RD. et al. In vivo regulation of P_ adrenergic receptors on human mononuclear leukocytes: assessment of receptor number, location, and function after posture change, exercise, and isoproterenol infusion. J Clin Endocrinol Metab 1986;63:847-53.
94
January
I 94-S
ecre RALF POLIKAR,
MD, BRIAN KENNEDY,
,
PHD, ALAN
JOHANA SMITH, RN, HOWARD DITTRICH,
MD, FACC, PASCAL NICOD,
San Diego. California
Cardiovascularsensitivityto catecholamineswas assess4 in 15 patientswith hypothyroidism(mean [f SEMIthyroxine [Td] index 2.7 i 0.5 pg/loO ml, thyroid stimulating
hormone[TSH] 136.9 + .3 /.&J/ml),aged 45 f and ia 8 healthycontrolsubjects.The study was repeatedin 10 patients with hypothyroidism4.0 f 0.5 months after 2.1 #q/loo thyroid replacementtherapy (T4 index averageand mi, TSH3.5 f 1.3 @J/ml).In addition, maximalheart rates were measuredusing 24 h ambulatory electrocardiographic (KG) monitoring,and plasmalevels of ephrephrineand norepinephrinewere determinedbefore and after thyroid replacement. Heartrate increasedless afterbolus injectionof 0.8,1.6 and 3.2 jqgof isoprotereoolin the hypothyroid(10 f 2,15 P 2 and 21 i 4 beats/n@ respectively) than in tne
tively) state (p C
0.05).
ear&c cbroaotro muximaldaily heart rates seen in roidism, whichoccursdespite eleva rine levels.
euthyroid(16 f 3,22 i 3 and 30 I 4 beats/min,respec-
Patients with hypothyroidism often present with bradycardia, ptosis of the eyelids and other signs of low sympathetic activity (1). However, their plasma norepinephrine and epinephrine levels are high (2,3), suggesting decreased catecholamine sensitivity. The numerous studies (4-13) of beta-adrenergic responsiveness in various animal models of hypothyroidism have had conflicting results. Similarly, whether decreased sensitivity to beta-adrenergic stimulation is present in patients with hypothyroidism is still controversial (14-17). Therefore, this study assessed the heart rate response to beta-adrenergic stimulation of patients with hypothyroidism before and after thyroid replacement therapy.
From the Divisions of Cardiology and Nephrology. University of California-San Diego Medical Center and Veterans Administration Medical Center, San Diego, California. This study was supported in part by Grant HL 35924 and Clinical Research Center Grant MO1 RR 00827 from the National Institutes of Health, Bethesda, Maryland. Manuscript received March 20,198% revised manuscript received July 26, 1989, accepted August 8. 1989. Address for: Ralf Polikar, MD, Division of Cardiology, University of Cahfomia-San Diego Medical Center. 225 Dickinson Street, H-81 I-A, San Diego, California 92103. 01990 by the American College of Cardiology
Study patients. Fifteen patients (4 men and ii women), aged 27 to 76 years (mean f SEM 45 * 4), with newly diagnosed hypothyroidis.n were enrolled in this study from August 1987to June 1988.No patient had cardiac disease or was receiving drugs that might interact with cardiac or autonomic nervous system function. All medications, except thyroxine, remained unchanged throughout the protocol. All patients gave written informed consent to this medical center’s Httman Subjects Committee-approved protocol. Ten of the IS patients underwent both a baseline study in the hypothyroid state and a repeat study during thyroid replacement therapy with thyroxine 4 + 0.5 months after the baseline study. Five of the patients completed the baseline study, but refused to undergo a repeat study while in a euthyroid state. Eight healthy control subjects (three men and five women) with a mean age of 42 + 4 years and normal thyroid fu ts completed the same p All patients were admi search Center at 9:CWI AM in the morning and had an intravenous line inserted. Blood was drawn for thyroid function tests. Patients then rested supine for at least 2 h 073% 1097/901$3.50
JACC Vol. 15. MO. ! January I :94-s
ment well. Their mean weight of 83.7 t 7 kg at baseline
s were ana-
heart rate was automat~ca~~~ combated by using a 16 beat sliding average after checking for motion artifacts.
The isoproterenol infitsiun test gave reproducibleheart rates, with a variability between injections of 4 2 4 beats/
POLIKAR ET AL. HYPOTHYROIDISM AND SENSITIVITY
%
JAW Vol. 15. No. I January I 94-8
TO CATECHOLAMINES
Table 2. Decreases in Diastolic Blood Pressure (mm Hg) After Injection of Isoproterenol lsoproterenol 0.8 pg
patientswithhypothyroidism tn = 10) PaGentsin a hypolhyroid state (n = 7)*
All
Patients in a euthyroid state (n = 7)* Control subjects (n = 8)
1.6 j.~6
3.2 erg
2
13 f 2
16 i 4
422 IO + 2 12 + 2
14 f 3 20 f 5 22 2 4
20 + 5 31 r1 22 + 6
4 2
*Seven paGents studied before and abler replacement therapy.
therapy. Seven patients with hypothyroidism required 4.4 ccg and three required 12.8 clg of isoproterenol before thyroid replacement. After thyroid replacement, only two patients required 6.4 cogand none required 12.8 M. The increase in heart rate was also significantly lower w”lenall 15 patients with hypothyroidism were compared with the control subjects (Fig. 2). There was no significant correlation between the degree of hypothyroidism, assessed by T4 index and TSH levels, and the heart rate increase after injections of isoproterenol.
0-
WPO
Euth
Figure 1. Plasma levels of norepinephrine measured before (Hype) and after (Euth) thyroid replacement in IO patients with hypothy
roidism.
min (mean + SD). Patients reported minor side effects of palpitation (eight patients), deep sighing (eight patients), anxiety (five patients) and flushing (three patients). After injection of saline solution, the average increase in heart rate was 3 + 1 beat&n (mean k SEM). Injections of 0. I to 0.4 pg of isoproterenol resulted in only a minimal increase in heart rate in patients with hypothyroidism and control subjects (Fig. 2). After injection of 0.8, 1.6 and 3.2 H of isoproterenol, the increase in heart rate was significantly blunted in patients who had not yet received replacement
Baseline blood pressure measurements were similar in patients in the hypothyroid and the euthyroid state (125 rt 8/83 k 5 versus 127 2 7183 -I 6 mm Hg). Decreases in
diastolic blood pressure during isoproterenol infusion tended to be smaller in patients with hypothyroidism than in patients in the euthyroid state or in control subjects, although these differences did not reach statistical significance (Table 2). However, the changes in blood pressure during the
I-
40
NS
-I
30 20
Figure 2. lsoproterenol (ISO) sensitivity test results. A, Ten patients studied both before (Hype)
IS0 1.6 mcg
T 156 6.4 mcg 30
:
20 10 40
7
i
01
HYPO
Euth
r
P’O.05
-I
-l T I-P’O.05
All Hypo Controls IS0 6.4 mcg 30
:
20
-
10
:
: *
0 I_-
HYPO Euth
IS0 3 2 mcg
All
Hypo Controls
and after (Euth) thyroid replacement. B, Fifteen patients with hypothyroidism (All Hype) and eight control subjects (Controls).
JACC Vol. 15, No. 1 January 1 :94-8
asal, average and maxilrd
hean rates recorded du61g 24
We ‘dIdIlk Ana Hefty
for her experl assistance in the preparation of the Wrighl, MD. Boyle Park, MD and Steve Carter. BS for their he;p in the realization of this project. and Wolfgang ~i~~rna~n, MD for his guidance.
manuscripl. We thank Michael
rine levels and increased cardiac cbronotro~ic res~o~s~veroidism. Furthermonitoring. Thyroid replacement
I. Klein I. Levey GS. New perspectives on thyroid amines and the heart. Am J Med 1984;76: 167-72.
hormone,
catecbol-
2. Christensen NJ. Plasma noradrenaline and adrenaline in patients with thyrotoxicosis and myxoedema. Clin Sci Mol Med 1973;45:161-3.
increased heart rate response to adrenergic stimuiat~o~. e contribution of these two -mechanisms
3. Manhem P, Hallengren B, Nansson BG. Plasma noradrenaline and blood pressure in hypothyroid patients: effect of gradual thyroxine treatment. Clin Endocrinol 1984:20:701-7. 4.
Its. Admi~jstrat~on
3ilezikian JP. Loeb JN. The influence of bype~byroid~sm and hypotby,oidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Endocrinol Rev 1983:414:378-87.
5. Banerjee SP. Kung LS. Beta-adrenergic receptors in rat heart: effects of thyroideclomy. Eur J Pharmacol 1977:43:207-8.
occurs in euthyroid rats (8,12) and a smaller ~hronotro~~~ response to isoproterenol (9.13). These differences may be due to a decrease in the number of beta-adrenergic receptors (5). Studies performed in paiients with hypothyroidism also
6. McConnaughey MM. Jones LR, Watanabe AM. Bescb LT, Lefkowitz RI. Thyroxine and propylthiouracil effecls on alpha- :*nd beta-adrenergic receptor number, ATPase activities. and sialic acid content of rat cardiac membrane vesicles. J Cardiovasc Pharmacol 1979:1:609-23.
98
POLIKAR ET AL. I-IYPOTHYROIDISMAND SENSITIVITY TO CATECHOLAMINES
7. Stiles GL, L&owitz RJ. Thyroid hormone modulation of agonist betaadrecergic receptor interactions in the rat heart. Life Sci 1981;28:252936. 8. Ciaraldi TP, Marinetti GV. Hormone action at the membrane level. VII!. Adrenergic receptors in rat heart and adipocytes end their modulation by thyroxine. Biochem Biophys Acta 1978:541:334-46. 9. Kunos G, Mucci L, O’Regan S. The influence of hormonal and neuronal factors on rat heart adrenoreceptors. Br J Pharmacol 1980;71:371-86. 10. Noguchi A, Whitsett JA. Ontogeny of alpha,-adnnergic receptors in the rat myocardium: effects of hypothyroidism. Eur J Pharmacol 1983;86:4350. II. Williams RS, Lefkowitz RJ. The effect of thyroid hormone on adrenergic receptors. In: Oppenheimer JH. ed. Molecular Basis of Thyroid Hormone Action. London: Academic Press. 1983:325-49. 12. lshac BJN, Pennefather JN. Handberg GM. Effect of changes in thyroid state on atrial alpha- and beta-adrenoreceptors. adenylate cyclase activity, and catecholamine levels in the rat. J Cardiovasc Phanacol lY83:5: 3%-40X 13. Gross G, Lues 1. Thyroid-dependent alterations of myocardial adrenorecaptors and adrenoreceptor-mediated responses in the rat. Naunyn Schmiedebergs Arch Pharmacol 1985:329:427-39. 14. Harrison TS. Adrenal medullary and thyroid relationships. 1964;44:161-85. IS. Waldstein SS. Thyroid-catecholamine 17:123-33.
interrelations.
Pbysiol Rev
Ann Rev hied 1966;
16. Leak D, Lew M. Effect of treatmjent of hypothyroidism on circulatory response to adrenaline. Br Heart J 1%2;25:30-4. 17. McDevitt
ffi,
Riddell JG. Hadden
DR, Montgomery
DAD. Catechol-
JACC Vd. 15, No. I January 199tk94-8
amine sensitivity in hyperthyroidism and hypotbyroidism. Br 3 Clin Pharmacol 1978:6:297-301. 18. Cleaveland CR, Rangno RE. Shand DG. A standardized isoproterenol sensitivity test. Arch Intern Med 1972;130:47-52. 19. Chopra LJ, Solomon DH, Ho RS. A radioimmtinoassay of thyroxine. J Clin Endocrinol Metab 1971;33:865-8. 20. Stein RB, Price L. Evaluation of adjusted total thyroxine (free thyroxine
index) as a measure of thyroid function. J Clin P .ocrinol Metab 1972;34:225-8. 21. Larsen PR, Alexander NM, Chopra IJ, et al. Revised nomenclature for tests of thyroid hurmones and thyroid-related proteins in serum. J Clin Endocrinol Metab 1987:64:1089-92. 22. Ziegler MG, Woodson LC, Kennedy B. Radioenzymatic assay of catecholamines. metabolites and related e!?zymes. In: Krstulovic AR, ed. Quantitative Analysis of Catecholamines and Related Compounds. New York: John Wiley, 1986:263-80. 23. Polikar R, Feld GK. D&rich HC, Smith J, Nicod P. Effect of thyroid replacement therapy on the frequency of benign atrial and ventrl:ular arrhythmias. J Am Co8 Cardiol 1989;14:9YY-1002. 24. Freedberg AS. Papp JG, Vaughan Williams EM. The effect of altered thyroid state on atrial intracellular potentials. J Physiol 1970;207:357-69. 25. Maisel AS, Ziegler MG. Carter S, Insel PA. Motulsky HJ. In vivo regulation of Badrenergic receptors on mononuclear leukocytes and heart. J Clin Invest 1988;82:2038-44. 26. DeBlasi A, Maisel AS. Feldman RD. et al. In vivo regulation of P_ adrenergic receptors on human mononuclear leukocytes: assessment of receptor number, location, and function after posture change, exercise, and isoproterenol infusion. J Clin Endocrinol Metab 1986;63:847-53.