Anti-Hypertensive Treatment Preserves Appetite Suppression While Preventing Cardiovascular Adverse Effects of Tesofensine in Rats
Anti-Hypertensive Treatment Preserves Appetite Suppression While Preventing Cardiovascular Adverse Effects of Tesofensine in Rats
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DOI：
10.1002/oby.20122
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发表时间：
2013-05-01
期刊：
影响因子：
6.9
通讯作者：
Hansen, Henrik H.
中科院分区：
文献类型：
--
作者：
Bentzen, Bo Hjorth;Grunnet, Morten;Hansen, Henrik H.
目的：特索芬新是一种新型的三重单胺再摄取抑制剂，用于治疗肥胖症。临床前和临床数据表明，食欲抑制是特索芬新发挥其强大减肥作用的重要机制。值得注意的是，对特索芬新治疗的强烈的低吞噬反应被证明与去甲肾上腺素能和多巴胺能神经传递的中枢刺激有关。tesofensine的拟交感神经作用模式也可能与临床环境中观察到的心率和血压升高有关，因此，我们试图通过实验来解决这个问题。设计和方法：在联合实时食物摄入和心血管遥测监测系统中，在遥测清醒大鼠中同时研究tesofensine的促肾上腺皮质激素和心血管作用。急性给药的tesofensine引起剂量依赖性hypophagic效应，以及增加心率和血压。有趣的是，与美托洛尔（B（1）肾上腺素受体阻滞剂，10-20 mg/kg，p.o.）完全防止了特索芬新的心血管交感作用，同时保持对食物摄取的强抑制功效不受影响。同样，血管紧张素AT（1）受体拮抗剂替米沙坦（1.0-3.0 mg/kg，p.o.）并不干扰替索芬辛的减肥作用，但替米沙坦仅部分逆转替索芬辛引起的收缩压升高，对心率升高无影响。结论：这些数据表明，tesofensine通过增加交感神经活动引起心率和血压升高，并且不同的肾上腺素受体亚型可能负责特索芬新的抗肥胖和心血管作用。
Objective: Tesofensine is a novel triple monoamine reuptake inhibitor which is in development for the treatment of obesity. Preclinical and clinical data suggest that appetite suppression is an important mechanism by which tesofensine exerts its robust weight reducing effect. Notably, the strong hypophagic response to tesofensine treatment is demonstrated to be linked to central stimulation of noradrenergic and dopaminergic neurotransmission. The sympathomimetic mode of action of tesofensine may also associate with the elevated heart rate and blood pressure observed in clinical settings, and we therefore sought experimentally to address this issue.Design and Methods: The anorexigenic and cardiovascular effects of tesofensine were studied simultaneously in telemetrized conscious rats in a combined real-time food intake and cardiovascular telemetry monitoring system.Results: Acute administration of tesofensine caused a dose-dependent hypophagic effect as well as increased heart rate and blood pressure. Interestingly, combined treatment with metoprolol (b(1) adrenoceptor blocker, 10-20 mg/kg, p.o.) fully prevented the cardiovascular sympathetic effects of tesofensine while leaving the robust inhibitory efficacy on food intake unaffected. Similarly, the angiotensin AT(1) receptor antagonist telmisartan (1.0-3.0 mg/kg, p.o.) did not interfere with the anti-obesity effects of tesofensine, however, telmisartan only partially reversed the increase in systolic blood pressure and had no effect on the elevated heart rate induced by tesofensine.Conclusion: These data suggests that tesofensine causes elevations in heart rate and blood pressure by increasing sympathetic activity, and that different adrenoceptor subtypes may be responsible for the anti-obesity and cardiovascular effects of tesofensine.