Laugero Kevin D, Stonehouse Anthony H, Guss Stacy, Landry Jannine, Vu Calvin, Parkes David G
Amylin Pharmaceuticals Inc., San Diego, California, USA.
Metab Syndr Relat Disord. 2009 Aug;7(4):327-34. doi: 10.1089/met.2008.0095.
Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon like peptide 1 (GLP 1) in rats. However, there are limited studies testing the chronic effects of these peptides on arterial pressure and no reports showing the effects of these peptides to reverse hypertension in the context of the metabolic syndrome.
Thus, we examined the response to peripheral exenatide using telemetry in conscious, unrestrained rats under normotensive conditions and in a model of hypertension/metabolic syndrome induced by corticosterone. Rats were implanted with either corticosterone or wax (control) pellets, followed 14 days later by the additional implantation of pumps to deliver exenatide (1 microg/kg per day) or vehicle for 7 days.
The 21-day corticosterone treatment produced hypertriglyceridemia, visceral fat deposition, hyperglycemia, insulin resistance, and an elevation of mean arterial blood pressure (MAP) by 14 +/- 1 mmHg. Exenatide significantly reversed corticosterone-induced increases in blood pressure and this normalization occurred independently from change in body weight. Additionally, exenatide reduced MAP by 5 +/- 3 mmHg in normotensive control rats.
These results are the first demonstration of a durable antihypertensive effect of exenatide in a glucocorticoid-induced model of the metabolic syndrome.
艾塞那肽是一种肽类肠促胰岛素类似物，具有与体重减轻相关的血糖调节作用。先前的报告表明，在大鼠体内全身或脑室内给予艾塞那肽或胰高血糖素样肽1（GLP-1）后，血压会急性升高。然而，测试这些肽对动脉血压慢性影响的研究有限，且没有报告显示这些肽在代谢综合征背景下逆转高血压的作用。
因此，我们在正常血压条件下以及在由皮质酮诱导的高血压/代谢综合征模型中，使用遥测技术检测清醒、不受约束的大鼠对周围给予艾塞那肽的反应。给大鼠植入皮质酮或蜡丸（对照），14天后再额外植入泵，以持续7天给予艾塞那肽（每天1微克/千克）或赋形剂。
21天的皮质酮治疗导致高甘油三酯血症、内脏脂肪沉积、高血糖、胰岛素抵抗，平均动脉血压（MAP）升高14±1毫米汞柱。艾塞那肽显著逆转了皮质酮诱导的血压升高，且这种血压正常化与体重变化无关。此外，艾塞那肽使正常血压对照大鼠的MAP降低了5±3毫米汞柱。
这些结果首次证明了艾塞那肽在糖皮质激素诱导的代谢综合征模型中具有持久的降压作用。
