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Sympathomimetic agents and T3 lead to similar cardiac symptoms,
especially inducing tachycardia and increasing the force and velocity of
cardiac contraction. Treatment of H patients with sympatholytic agents
ameliorates rate- related cardiac changes. These observations have strengthened
the hypothesis that some T3 effects are mediated by an increased
activity of the sympathoadrenal system or an increased responsiveness and
sensitivity of cardiac tissue to normal sympathomimetic stimuli (25). Since
plasma and urine levels of cathecolamines are normal in H, the hypothesis
that the thyroid status leads to an increased sensitivity of the sympathoadrenal
system has been favoured. The enhanced sympathetic sensitivity of the H
heart may be mediated by an increased number of b adrenergic receptors
(26,27). In humans, short-term H is associated with an increase of the
sensitivity of heart rate and left ventricular shortening velocity to isoproterenol
stimulation (28). In addition, an increase level of other components of
the sympathetic transmission system occurs. Specifically, investigations
in H pigs show that T3 markedly increases the amount of stimulatory
guanine nucleotide regulatory protein (29). Thus, enhanced sympathetic
sensitivity in H is most likely mediated by an increase in the number of
both b receptors and guanine regulatory proteins.
Cardiac tissue contains both b1- and b2-adrenergic receptor subtypes (30,31). In most species studied, the b1-receptors predominant accounting for 70% of total b-adrenergic receptors. Furthermore, b-adrenoceptors are increased approximately 2-fold in the sinoatrial node compared to surrounding myocytes. The proportion of b1-adrenoceptors in the sinoatrial node is comprised predominantly of b1- receptors (75%). In contrast, b2-receptors are the predominant species in nonmyocyte vascular cells (75%). Thus, b1-receptors are the predominant ß- adrenoceptors in cells of myocyte origin, and might be responsive to T3 regulation. Indeed, there appears to be a differential induction of cardiac b1- and b2-adrenergic receptor mRNA in rat myocytes by T3 (32). T3 causes a 4-fold induction of cardiac b1-adrenoceptor mRNA, but no significant change in b2- receptor mRNA. The effects of T3 on b1-adrenergic gene transcription occurs within 30 minutes, elevations lasting for 72 hrs. Following the rise in b1-mRNA, there is a 3-fold increase in the density of cardiac b1-receptors which persists for 48 hr. In contrast, b2-receptors are not significantly increased following T3 administration. These studies suggest that in cardiac tissue, the b1- adrenergic receptor gene is sensitive to T3, whereas the b2-receptor gene is influenced minimally. Extrapolation of these animal and in vitro studies to the human heart is premature since cardiac b1-receptor gene regulation by T3 in hypo humans has not been studied. However, Ladenson et al. (13), have shown that the cardiac b2-adrenergic receptor in hypo is refractory to T4 therapy as determined by PCR amplification of the b2-mRNA in cardiac tissue from a hypo subject before and after therapy. |
