Cardiac action of thyroxin and myocardial catecholamines
It has long been known that the thyroid hormones are important in the regulation of hemodynamic response to epinephrine or norepinephrine. A total or near total sympathetic block, produced either by the subarachnoid injection of procaine(Knight, 1945) or by the intravenous injection of hexamethonium (Ramey et al. 1995), has been reported to be effective both in preventing or abolishing the physiologic manifestation of thyrotoxic crisis. Brewster et al.(1956) thus suggested that the cardiac effects of thyrotoxicosis are not the result of the thyroid hormones per se, but rather are due to the effects of epinephrine and the norepinephrine as augmented by the thyroid hormones. On the other hand, a direct effect of thyroid hormone on heart rate is suggested from studies by Hirvonen and Lyback (1956) in isolated atria preparations. These authors recorded the rate of contraction of atria taken from hyperthyroid rats as a function of temperature. Rate of beat at various temperatures in thyroid-treated animals was shown to be greater than in control animals. This experiment, however, do not exclude a possible influence of myocardial catecholamines on the heart rate.
While examining effects of various drugs on myocardial catecholamine content, it was found that thyroxin produced a significant increase of catecholamines in myocardium. This finding led to examine the relationship between thyroxin and the
norepinephrine on the heart, with special referrence to the myocardial catecholamines.
Methods and Materials
Atria isolated from rabbits treated with various drugs were employed in this experiment. The heart was rapidly removed from rabbits under ether anesthesia.
Ventricular muscle, connective tissue, fat and blood vessels were excised from the atria which were then suspended in muscle chamber containing 100ml of Tyrode's solution maintained at constant temperature of 38℃. Oxygen was bubbled through the
bathing fluid via a sintered glass plate at the bottom of the chamber. Isotonic contractile amplitude of spontaneous beat was recorded on a smoked drum by means of a lever. After being washed several times with Tyrode's solution, the atria attain a constant rate and amplitude of contraction. At this time the rate of contraction was considered as initial heart rate of the atria. Thereafter, drugs were added to the bath and the changes of contractile amplitude and rate of spontaneous beat were expressed as per cent changes relative to those prior to the addition of the drugs.
The catecholamine content of cardiac muscle was determined to the spectrophotofluorometric procedure described by Shore and Olin(1958).
Results and Conclusion:
1. Rabbits were made hyperthyroid by intraperitoneal injection of thyroxin 2.0gm/kg for three successive days. The atria isolated from these rabbits beated consistantly faster than atria from normal and the cardiac activity of norepinephrine was observed to be significantly increased in these atria. Myocardial catecholamine content of the thyroxin-treated rabbits was markedly increased compared to that of normal rabbits.
2. Thyroxin exerted little or no effects on the isolated atria from normal rabbits at concentrations below 5×10**-5 M. However, following the administration of thyroxin (5×10**-5 M), the cardiostimulant response of the atria to norepinephrine was significantly augmented. Similar augmentation of the cardiostimulant activity of norepinephrine was observed in the atria pretreated with ethylenediamine tetraacetic acid (EDTA) 10**-5 M which alone has no effect, and in the presence of EDTA, thyroxin failed to augment the cardiac activity of norepinephrine. This result suggests that the augmentation of the activity of norepinephrine is not due to the direct action of thyroxin on the atria but rather due to the supression of autoxidation of norepinephrine through the chelation of metal ions in Tyrode's solution. Consequently the interaction of thyroxin and norepinephrine may be different between in vivo and in vitro.
3. Numerous investigators (Moon and turner, 1959; Mayer et al., 1956; De Felice et al., 1957) have demonstrated that reserpine exerts antithyroid activity. Reserpine 1gm/kg was injected intraperitoneally into rabbits and the animals were killed 24 hours after the infection. The myocardial catecholamine content of these animals was markedly depleted and the rate of contraction of the atria isolated from these reserpine-treated rabbits was found to be significantly slower than normal rabbits atria.
In an attempt to determine the influence of reserpine on the cardiac activity of thyroxin, rabbits were injected intraperitoneally with thyroxin 2gm/kg for 3 successive days and with reserpine 1gm/kg on 3rd day. The atria isolated from these
animals exhibited bradycardia similar to that seen in the atria of rabbits treated with reserpine alone. Examination of myocardial catecholamines of rabbits treated with thyroxin and reserpine revealed a marked depletion.
This results may suggest that the bradycardia of the atria from rabbits treated with thyroxin and reserpine could be due to reserpine action operating through myocardial catecholamine depletion.
4. Rabbits were made hypothyroid by oral administration of prophlthiouracil 50gm for 14 days. The myocardial catecholamine content and the rate of beat of the isolated atria in these animals were not different from those observed in normal rabbits respectively. The response of the atria to norepinephrine was also not changed.
5. Experiments was conducted on the thyroidectomized rabbits. The rate of beat and the response to norepinephrine of the atria isolated from these rabbits were similar to those of the atria from normal rabbits. Myocardial catecholamines were only slightly decreased in two out of four thyroidectomized rabbits.
6. Rabbits were made also hypothyroid by the intravenous injection of 10 milicurie of I**131 approximately 53 days prior to the test. The tate of beat and the response to norepinephrine of the atria isolated from these animals were not different from those of the atria from normal rabbits respectively. Myocardial catecholamines were slightly decreased in one out of three rabbits.
In summary, the data presented above serve to emphasize three points: 1) tachycardia and the enhanced cardiac response to norepinephrine are seen only in vivo but not in vitro by the administration of thyroxin; 2) the administration of thyroxin in vivo causes a significant increase in myocardial catecholamines and 3) reserpine decrease myocardial catecholamine content and abolish the cardiac activity of thyroxin.
From these results it may be concluded that the hemodynamic activity of thyroxin may be dependent on an increase in myocardial catecholamines.