Zwaveling J, Batink H D, de Jong J, Winkler Prins E A, Pfaffendorf M, van Zwieten P A
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Dec;354(6):755-64. doi: 10.1007/BF00166902.
We investigated the influence of hyper- and hypothyroidism on basal parameters of isolated perfused hearts of rats. In addition the effects of different extracellular calcium concentrations ([Ca2+]o), the calcium entry promoter Bay K8644 and the alpha 1-adrenoceptor agonist methoxamine were investigated. Since alterations in alpha-adrenoceptor density could explain the increased sensitivity to methoxamine in hearts from hypothyroid rats, alpha 1-adrenoceptor density in the left ventricle was also established. Different time-schedules of exposure to hyper- and hypothyroidism were used to investigate whether the influence of chronic dysthyroid states on alpha 1-adrenoceptor density is transient and time-dependent. Simultaneously myocardial noradrenaline and adrenaline tissue concentrations were determined, since they might correlate with the observed changes. Hyperthyroidism was induced by feeding rats for 1, 4 and 8 weeks with 5 mg/kg L-thyroxine (T4)-containing rat chow. Hypothyroid rats were obtained by adding 0.05% propylthiouracil (PTU) to the drinking water during 1, 4 and 8 weeks. For the functional experiments animals were treated during 4 weeks, to mimic the clinical situation of a chronic endocrine disease. Langendorff hearts from hyperthyroid hearts showed an increased maximally developed relaxation velocity, whereas Langendorff hearts from hypothyroid rats showed an increased left ventricular pressure (LVP). We observed an increased maximal inotropic response to [Ca2+]o in hearts from both hyperthyroid and hypothyroid rats, indicating that both dysthyroid states interfere with the handling of calcium ions by the contractile apparatus. Unchanged responses to Bay K8644 in hearts from hyperthyroid and depressed responses in hearts from hypothyroid rats suggest that the involvement of L-type calcium channels is rather unlikely. Furthermore, the reflex increase in coronary flow in response to enhanced contractile force appeared to fail in hearts from hypothyroid rats. Sensitivity of the response to methoxamine was increased in hearts from hypothyroid rats, which was accompanied by a decrease in the number of myocardial alpha 1-adrenoceptors. Both T4 and PTU treatment resulted in a non-transient decrease of alpha 1-adrenoceptor density in left ventricular tissue. Furthermore, hypothyroidism increased the percentage of alpha 1A-binding sites, whereas in hyperthyroidism the distribution of the alpha 1-adrenoceptor subtypes was not affected. Myocardial tissue concentrations of noradrenaline and adrenaline were unchanged in hyperthyroid rats and decreased in hypothyroid rats. The present study indicates that thyroid hormones have a direct rather than a sympathetically mediated effect on alpha 1-adrenoceptor mediated myocardial functions.
我们研究了甲状腺功能亢进和减退对大鼠离体灌注心脏基础参数的影响。此外，还研究了不同细胞外钙浓度（[Ca2+]o）、钙内流促进剂Bay K8644以及α1-肾上腺素能受体激动剂甲氧明的作用。由于α-肾上腺素能受体密度的改变可能解释甲状腺功能减退大鼠心脏对甲氧明敏感性增加的原因，因此还测定了左心室中的α1-肾上腺素能受体密度。采用不同的甲状腺功能亢进和减退暴露时间方案，以研究慢性甲状腺功能紊乱状态对α1-肾上腺素能受体密度的影响是否是短暂的且与时间相关。同时测定心肌去甲肾上腺素和肾上腺素的组织浓度，因为它们可能与观察到的变化相关。通过给大鼠喂食含5mg/kg L-甲状腺素（T4）的大鼠饲料1、4和8周来诱导甲状腺功能亢进。通过在1、4和8周内给饮用水中添加0.05%丙硫氧嘧啶（PTU）来获得甲状腺功能减退大鼠。为进行功能实验，对动物进行4周的处理，以模拟慢性内分泌疾病的临床情况。甲状腺功能亢进大鼠的Langendorff心脏显示最大舒张速度增加，而甲状腺功能减退大鼠的Langendorff心脏显示左心室压力（LVP）增加。我们观察到甲状腺功能亢进和减退大鼠的心脏对[Ca2+]o的最大正性肌力反应均增加，表明两种甲状腺功能紊乱状态均干扰收缩装置对钙离子的处理。甲状腺功能亢进大鼠心脏对Bay K8644的反应未改变，而甲状腺功能减退大鼠心脏的反应降低，这表明L型钙通道参与的可能性较小。此外，甲状腺功能减退大鼠心脏对增强收缩力的反应中，冠状动脉血流的反射性增加似乎失效。甲状腺功能减退大鼠心脏对甲氧明反应的敏感性增加，同时心肌α1-肾上腺素能受体数量减少。T4和PTU处理均导致左心室组织中α1-肾上腺素能受体密度的非短暂性降低。此外，甲状腺功能减退增加了α1A结合位点的百分比，而甲状腺功能亢进时α1-肾上腺素能受体亚型的分布未受影响。甲状腺功能亢进大鼠心肌组织中去甲肾上腺素和肾上腺素的浓度未改变，而甲状腺功能减退大鼠中则降低。本研究表明，甲状腺激素对α1-肾上腺素能受体介导的心肌功能具有直接而非交感神经介导的作用。
