Seppet E K, Kolar F, Dixon I M, Hata T, Dhalla N S
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Mol Cell Biochem. 1993 Dec 22;129(2):145-59. doi: 10.1007/BF00926363.
In order to examine the regulatory role of thyroid hormone on sarcolemmal Ca(2+)-channels, Na(+)-Ca2+ exchange and Ca(2+)-pump as well as heart function, the effects of hypothyroidism and hyperthyroidism on rat heart performance and sarcolemmal Ca(2+)-handling were studied. Hyperthyroid rats showed higher values for heart rate (HR), maximal rates of ventricular pressure development +(dP/dt)max and pressure fall -(dP/dt)max, but shorter time to peak ventricular pressure (TPVP) and contraction time (CT) when compared with euthyroid rats. The left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP), as well as aortic systolic and diastolic pressures (ASP and ADP, respectively) were not significantly altered. Hypothyroid rats exhibited decreased values of LVSP, HR, ASP, ADP, +(dP/dt)max and -(dP/dt)max but higher CT when compared with euthyroid rats; the values of LVEDP and TPVP were not changed. Studies with isolated-perfused hearts showed that while hypothyroidism did not modulate the inotropic response to extracellular Ca2+ and Ca2+ channel blocker verapamil, hyperthyroidism increased sensitivity to Ca2+ and decreased sensitivity to verapamil in comparison to euthyroid hearts. Studies of [3H]-nitrendipine binding with purified cardiac sarcolemmal membrane revealed decreased number of high affinity binding sites (Bmax) without any change in the dissociation constant for receptor-ligand complex (Kd) in the hyperthyroid group when compared with euthyroid sarcolemma; hypothyroidism had no effect on these parameters. The activities of sarcolemmal Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake and ouabain-sensitive Na(+)-K+ ATPase were decreased whereas the Mg(2+)-ATPase activity was increased in hypothyroid hearts. On the other hand, sarcolemmal membranes from hyperthyroid samples exhibited increased ouabain-sensitive Na(+)-K+ ATPase activity, whereas Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake, and Mg(2+)-ATPase activities were unchanged. The Vmax and Ka for Ca2+ of cardiac sarcolemmal Na(+)-Ca2+ exchange were not altered in both hyperthyroid and hypothyroid states. These results indicate that the status of sarcolemmal Ca(2+)-transport processes is regulated by thyroid hormones and the modification of Ca(2+)-fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.
为了研究甲状腺激素对肌膜钙通道、钠钙交换体和钙泵以及心脏功能的调节作用，研究了甲状腺功能减退和甲状腺功能亢进对大鼠心脏功能和肌膜钙处理的影响。与甲状腺功能正常的大鼠相比，甲状腺功能亢进的大鼠心率（HR）、心室压力最大上升速率+(dP/dt)max和压力最大下降速率-(dP/dt)max更高，但心室压力峰值时间（TPVP）和收缩时间（CT）更短。左心室收缩压（LVSP）和左心室舒张末期压力（LVEDP）以及主动脉收缩压和舒张压（分别为ASP和ADP）没有明显改变。与甲状腺功能正常的大鼠相比，甲状腺功能减退的大鼠LVSP、HR、ASP、ADP、+(dP/dt)max和-(dP/dt)max的值降低，但CT更高；LVEDP和TPVP的值没有变化。对离体灌注心脏的研究表明，虽然甲状腺功能减退不会调节对细胞外钙和钙通道阻滞剂维拉帕米的变力反应，但与甲状腺功能正常的心脏相比，甲状腺功能亢进会增加对钙的敏感性并降低对维拉帕米的敏感性。用[3H]-尼群地平与纯化的心肌肌膜结合进行的研究表明，与甲状腺功能正常的肌膜相比，甲状腺功能亢进组高亲和力结合位点（Bmax）数量减少，而受体-配体复合物的解离常数（Kd）没有变化；甲状腺功能减退对这些参数没有影响。甲状腺功能减退的心脏中，肌膜钙刺激的ATP酶、ATP依赖性钙摄取和哇巴因敏感的钠钾ATP酶的活性降低，而镁ATP酶活性增加。另一方面，甲状腺功能亢进样本的肌膜显示哇巴因敏感的钠钾ATP酶活性增加，而钙刺激的ATP酶、ATP依赖性钙摄取和镁ATP酶活性没有变化。在甲状腺功能亢进和甲状腺功能减退状态下，心肌肌膜钠钙交换体的钙的Vmax和Ka均未改变。这些结果表明，肌膜钙转运过程的状态受甲状腺激素调节，跨肌膜钙通量的改变可能在甲状腺状态依赖性心脏收缩变化的发展中起关键作用。
