Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN.
Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
J Am Heart Assoc. 2018 Feb 25;7(5):e008000. doi: 10.1161/JAHA.117.008000.
Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity.
Healthy adults participated in a 2-part double-blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (=0.01 versus placebo) and increased tPA (<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (=0.04 versus sitagliptin alone) and increased stimulated GH (<0.01), but decreased vascular resistance (=0.01) such that nadir vascular resistance correlated inversely with GH (=-0.90, <0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA.
Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.
生长激素（GH）减少与内皮功能障碍和纤维蛋白溶解受损有关。生长激素释放激素是 GH 分泌的主要刺激物，也是二肽基肽酶-4 的底物。我们检验了这样一个假设，即使用西他列汀抑制二肽基肽酶-4 会增加刺激后的 GH 分泌、血管舒张和组织纤溶酶原激活物（tPA）活性。
健康成年人参加了一项 2 部分双盲、随机、安慰剂对照、交叉研究。首先，39 名患者（29 名女性）在洗脱期之间的 2 天中每天接受西他列汀或安慰剂治疗。在研究药物给药后 1 小时，采集血液，然后给予精氨酸（30g IV）以刺激 GH。通过体积描记法评估血管舒张，并采集血液 150 分钟。洗脱后，29 名女性中的 19 名接受了单独的西他列汀或西他列汀加拮抗剂，以阐明 GH 受体（GHR）（n=5）、一氧化氮（n=7）或胰高血糖素样肽-1 受体（n=7）依赖性作用。西他列汀增强了女性的刺激后 GH 分泌（<0.01 与安慰剂相比，30 分钟）和游离胰岛素样生长因子-1（<0.001 与安慰剂相比，经基线调整后）。所有患者的血管舒张和 tPA 均增加，但西他列汀仅增强女性的血管舒张（=0.01 与安慰剂相比）和增加 tPA（<0.001）。GHR 阻断减少了游离胰岛素样生长因子-1（=0.04 与单独西他列汀相比）并增加了刺激后的 GH（<0.01），但降低了血管阻力（=0.01），使得血管阻力的最低值与 GH 呈负相关（=-0.90，<0.001）。GHR 阻断抑制了 tPA。一氧化氮或胰高血糖素样肽-1 受体阻断均不影响血管舒张或 tPA。
西他列汀增强了女性的刺激后 GH、血管舒张和纤维蛋白溶解。在西他列汀治疗期间，游离胰岛素样生长因子-1 和 tPA 的增加是通过 GHR 发生的，而血管舒张与 GH 相关，但通过 GHR 非依赖性机制发生。
