Neumann Joachim, Hofmann Britt, Kirchhefer Uwe, Gergs Ulrich
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Straße 4, 06097, Halle (Saale), Germany.
Department of Cardiac Surgery, Mid-German Heart Centre, University Hospital Halle, Ernst-Grube Straße 40, 06097, Halle (Saale), Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 29. doi: 10.1007/s00210-025-04214-8.
Tirzepatide is an approved drug that is used to treat type 2 diabetes. Tirzepatide is a peptide comprised of 39 amino acids and activates glucose-dependent insulinotropic polypeptide receptors (GIPR) and glucagon-like peptide-1 receptors (GLP-1R). Via GIPR and GLP-1R, tirzepatide stimulated in cell culture adenylyl cyclases (AC) and thereby elevated the cellular content of 3':5' cyclic adenosine monophosphate (cAMP). We tested the hypothesis that tirzepatide augmented the force of contraction (FOC) in isolated electrically driven (1 Hz) human right atrial preparations (HAP) obtained during open heart surgery from adult patients. Cumulatively applied tirzepatide, starting at nanomolar concentrations, raised FOC in a concentration-dependent manner and a time-dependent manner (p < 0.05). The positive inotropic effects (PIE) of tirzepatide were attenuated by about a quarter by a GIPR antagonist (100 nM, Pro3-GIP) and by about three quarters by a GLP-1R antagonist (100 nM, exendin9-39) in HAP. Tirzepatide (1 µM) was less effective than 1 µM isoprenaline in raising FOC in HAP. The inhibitor of the cAMP-dependent protein kinase called H89 reversed the PIE of tirzepatide. We suggest that tirzepatide probably acts via stimulation of GIPR and GLP-1R to exert a PIE in HAP.
替尔泊肽是一种已获批准用于治疗2型糖尿病的药物。替尔泊肽是一种由39个氨基酸组成的肽，可激活葡萄糖依赖性促胰岛素多肽受体（GIPR）和胰高血糖素样肽-1受体（GLP-1R）。通过GIPR和GLP-1R，替尔泊肽在细胞培养中刺激腺苷酸环化酶（AC），从而提高细胞内3':5'环磷酸腺苷（cAMP）的含量。我们检验了以下假设：替尔泊肽可增强从成年患者心脏直视手术中获取的离体电驱动（1赫兹）人右心房标本（HAP）的收缩力（FOC）。从纳摩尔浓度开始累积应用替尔泊肽，以浓度依赖性和时间依赖性方式提高FOC（p < 0.05）。在HAP中，GIPR拮抗剂（100 nM，Pro3-GIP）使替尔泊肽的正性肌力作用（PIE）减弱约四分之一，而GLP-1R拮抗剂（100 nM，艾塞那肽9-39）使其减弱约四分之三。在提高HAP的FOC方面，1 μM替尔泊肽的效果不如1 μM异丙肾上腺素。名为H89的cAMP依赖性蛋白激酶抑制剂可逆转替尔泊肽的PIE。我们认为，替尔泊肽可能通过刺激GIPR和GLP-1R发挥作用，从而在HAP中产生PIE。
