College of Health Sciences, University of Wyoming, Laramie, WY 82071, USA.
J Neuroendocrinol. 2011 May;23(5):456-63. doi: 10.1111/j.1365-2826.2011.02119.x.
Gonadotrophin-releasing hormone (GnRH) is a hypothalamic hormone transported by the hypophyseal portal bloodstream to the pituitary gland, where it binds to GnRH receptors. However, GnRH receptors are expressed in multiple extrapituitary tissues, although their physiological relevance is not fully understood. GnRH agonists are employed extensively in steroid deprivation therapy, especially to suppress testosterone in prostate cancer. Because GnRH agonist treatment is associated with increased coronary heart disease and myocardial infarction, we investigated the impact of GnRH on cardiomyocyte contractile function. Cardiomyocytes were isolated from mouse hearts and mechanical and intracellular Ca(2+) properties were evaluated, including peak shortening amplitude (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90) ), maximal velocity of shortening/relengthening (± dLdt), electrically-stimulated rise in Fura-2 fluorescence intensity (ΔFFI) and Ca(2+) decay. GnRH (1 ng/ml) increased PS, ± dL/dt, resting FFI and ΔFFI, and prolonged TPS, TR(90) and Ca(2+) decay time, whereas 1 pg/ml GnRH affected all these cardiomyocyte variables, except TPS, resting FFI and ΔFFI. A concentration of 1 fg/ml GnRH and the GnRH cleavage product, GnRH-[1-5] (300 pg/ml), had no effect on any cardiomyocyte parameter. The 1 pg/ml GnRH-elicited responses were attenuated by the GnRH receptor antagonist cetrorelix (10 μm), the protein kinase A (PKA) inhibitor H89 (1 μm) but not the protein kinase C inhibitor chelerythrine chloride (1 μm). These data revealed that GnRH is capable of regulating cardiac contractile function via a GnRH receptor/PKA-dependent mechanism. If present in the human heart, dysfunction of such a system may play an important role in cardiac pathology observed in men treated with GnRH agonists for prostate cancer.
促性腺激素释放激素（GnRH）是一种下丘脑激素，通过垂体门脉血液输送到垂体，在那里与 GnRH 受体结合。然而，GnRH 受体在多种垂体外组织中表达，尽管其生理相关性尚未完全阐明。GnRH 激动剂广泛应用于类固醇剥夺治疗，特别是抑制前列腺癌中的睾酮。由于 GnRH 激动剂治疗与冠心病和心肌梗死的风险增加有关，我们研究了 GnRH 对心肌细胞收缩功能的影响。从小鼠心脏中分离心肌细胞，并评估其机械和细胞内 Ca(2+)特性，包括峰缩短幅度（PS）、达到 PS 的时间（TPS）、90%复长时间（TR(90)）、缩短/复长的最大速度（± dLdt）、受电刺激的 Fura-2 荧光强度升高（ΔFFI）和 Ca(2+)衰减。1ng/ml GnRH 增加 PS、± dL/dt、静息 FFI 和 ΔFFI，并延长 TPS、TR(90)和 Ca(2+)衰减时间，而 1pg/ml GnRH 影响所有这些心肌细胞变量，除 TPS、静息 FFI 和 ΔFFI 外。1fg/ml GnRH 和 GnRH 裂解产物 GnRH-[1-5]（300pg/ml）对任何心肌细胞参数均无影响。1pg/ml GnRH 诱导的反应被 GnRH 受体拮抗剂 cetrorelix（10μm）、蛋白激酶 A（PKA）抑制剂 H89（1μm）减弱，但不被蛋白激酶 C 抑制剂 Chelerythrine Chloride（1μm）减弱。这些数据表明，GnRH 通过 GnRH 受体/PKA 依赖性机制调节心脏收缩功能。如果在人心肌中存在，这种系统的功能障碍可能在接受 GnRH 激动剂治疗前列腺癌的男性中观察到的心脏病理学中发挥重要作用。
