Thyroxin과 norepinephrine과의 相協作用에 關한 硏究

Abstract

[한글]

[영문]

Clinical and laboratory investigators have long recognized tachycardia and increased responsiveness to norepinephrine in thyrotoxic man and thyroxin-injected animals. Hoffman et al. (1947), Schneckloth et al. (1953) and Rosenblum et al. (1933) reported that the hemodynamic responses to opinepkrine and norepinephrine was exaggerated in the presence of hyperthyroidism. The physiologic manifestations of hyperthyroidism have been effectively eliminated by sympathetic block, either produced by the subarachnoid injection of procaine (Knight, 1945) or by injection of phenoxybenamine (Ramey et al., 1955). In reviewing the effects of thyroxin on cardiovascular system, Brewster et al. (1956) concluded that the hemodynamic

changes of thyrotoxicosis are not the result of the thyroidhormone per se, but rather are due to augmentation of the effects of epinephrine and norepinephrineby thyroid hormones. Although most of the recent studies involving thyroxin failed to

illustrate sensitization to norepinephrine by thyroxin (Van Der Schoot and Moran, 1965; Heaa and Shanfeld, 1965), Lee et al. (1965) demonstrated that isolated rabbit atria pretreated with thyroxin were characterized by an increased sensitivity to norepinephrine applied to the muscle bath. The latter investigators concluded that the increased sensitization to norepinephrine was presumed to he caused bychelation of metal contaminants in the nutrient solution.

While investigating the cardiac uptake of norepinephrine, it was found that thyroxin significantly inhibited the uptake of norepinephrine. This finding led to undertake this experiment in order to clarify the enhancement of sensitivity of heart to norepinephrine by thyronin.

The experiments were conducted on the isolated atria and isolated aortic strips of rabbit The catecholamine content in atria was determined by the spectrophotofluorometric procedure described by Shore and Olin (1958) and the monoamine oxidase activity was determined calorimetrically according to the

Procedure of Green and Haughton (1961), using mitochondria prepared from cardiac homogenates in 0.25 M sucrose.

Results and Conclusion

1. Thyroxin exerted essentially no effects on the isolated atria and aortic strips from normal rabbits. However, following the administration of thyroxin, the cardiostimulant response of the atria to norepinepkrine was significantly augmented. Similar augmentation of the contractive activity of norepinepkrine was

observed in the aortic strip pretreated with thyroxin.

2. Ethylenediamine tetraacetic acid (EDTA), at a concentration of 10**-5M, produced no effects on the isolated atria and aortic strips of rabbits. However, the responses of the atria and aorta to norepinephrine were significantly augmented in the presence of EDTA, similarly as those in the presence of thyroxin.

When Thyrode's solution treated with 10**-5M of EDTA was used as the balking fluid, thyroxingenerally failed to enhance the cardiostimulant response of the is Dlated atria and contractive response of the isolated aortic strips to norepinephrine. This results suggest that the augmentation of the activity of norepinephrine is largely due to the supression of autoxidation of norepinephrine through the chelation of metal contaminants in Tyrode's solution. However, in a few instances, thyrokinseems to enhance slightly the cardiovascular activity of norepinephrine even in the presence of EDTA. This appears to indicate that other

factors besides the supression of autoxidation of norepinepkrine may participate in augmenting the activities of norepinephrine by thyroxin.

3. The isolated atria from normal and reserpine pretreated rabbits can take up significant amounts of exogenous norepinephrine in vitro. Pretreatment of the atria with thyroxin markedly inhibitedtheir uptake of catecholamine following exposure to norepinephrine. Therefore, the observed enhancement by tkyroxin of the cardiostimulant response to norepinephrine could he at least partly due to the inhibition of cardiac uptake and subsequently to larger amount of exogenous norepinephrine available to act on the adrenergic receptors.

4. Thyrokin possesses no or little inhibitory capacity on the cardiac monoamine oxidase activity. This result excludes the possibility that thyroxin, by inhibiting MAO, protects the norepinephrine from enzymatic inactivation and thus increases the

concentration in the heart.

From the above results, it may be concluded that thyroxin, when added in vitro to isolated atria and aortic strips, causes an enhancement of the cardiovascular activities of norepinephrine. The enhancement is presumed to be caused largely by chelation of metal contaminants in the nutrient solution and partly by inhibition of cardiac uptake of norepinephrine.