Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK.
Wellcome Trust/MRC Institute of Metabolic Science (IMS), Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Mol Metab. 2020 Sep;39:101024. doi: 10.1016/j.molmet.2020.101024. Epub 2020 May 21.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects.
We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPG) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA.
Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPG neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPG neurons. PPG ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPG neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR.
These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPG neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPG neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
胰高血糖素样肽-1 受体激动剂（GLP-1RAs）被用作抗糖尿病药物，并被批准用于肥胖症治疗。然而，GLP-1RAs 也会影响啮齿动物和人类的心率（HR）和动脉血压（ABP）。虽然已知 GLP-1 受体（GLP-1R）的激活会增加 HR，但募集的回路尚不清楚，特别是尚不清楚 GLP-1RAs 是否激活脑源前胰高血糖素（PPG）神经元来产生这些影响。
我们研究了 GLP-1RAs 在麻醉成年小鼠中的心率影响。在另一项研究中，我们在植入生物遥测探针并注射 AAV-DIO-hM3Dq：mCherry 或 AAV-mCherry-FLEX-DTA 的清醒、自由活动的转基因 Glu-Cre 小鼠中操纵了孤束核（NTS）PPG 神经元（PPG）的活性。
全身给予 GLP-1RA Ex-4 可增加麻醉或清醒小鼠的静息心率，但对清醒小鼠的 ABP 无影响。这种作用被β-肾上腺素受体阻滞剂阿替洛尔阻断，但不受毒蕈碱拮抗剂阿托品的影响。此外，当 PPG 神经元被消融时，Ex-4 诱导的心动过速仍然存在，并且 Ex-4 不会诱导 PPG 神经元中神经元活性标志物 cFos 的表达。PPG 消融或通过 hM4Di 受体对这些神经元进行急性化学遗传抑制对静息 HR 没有影响。相反，化学遗传激活 PPG 神经元会增加静息 HR。此外，将 GLP-1 应用于 PPG 神经元的主要投射靶区蛛网膜下腔的胸中段脊髓会增加 HR。
这些结果表明，全身给予 Ex-4 或 GLP-1 以及化学遗传激活 PPG 神经元均可增加 HR。Ex-4 增加了脊髓心脏交感节前神经元的活性，而没有募集 PPG 神经元，因此可能再现了 PPG 神经元激活的生理效应。这些神经元因此在控制静息 HR 和 ABP 方面没有发挥重要作用，但能够引起心动过速，因此可能参与急性应激的心血管反应。
