Contractile Effects of Semaglutide in the Human Atrium

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2024 Sep 28

PMID 39339176

Authors

Joachim Neumann

Katarina Hadova

Jan Klimas

Britt Hofmann

Ulrich Gergs

Affiliations

Soon will be listed here.

Abstract

Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.

Citing Articles

Glucagon Can Increase Force of Contraction via Glucagon Receptors in the Isolated Human Atrium.

Neumann J, Schmidt F, Hofmann B, Gergs U Int J Mol Sci. 2025; 26(2.

PMID: 39859412 PMC: 11765814. DOI: 10.3390/ijms26020698.

References

Ban K, Kim K, Cho C, Sauve M, Diamandis E, Backx P . Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. Endocrinology. 2010; 151(4):1520-31. DOI: 10.1210/en.2009-1197. View

Wallner M, Kolesnik E, Ablasser K, Khafaga M, Wakula P, Ljubojevic S . Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium. J Mol Cell Cardiol. 2015; 89(Pt B):365-75. DOI: 10.1016/j.yjmcc.2015.09.018. View

Overgaard R, Navarria A, Ingwersen S, Baekdal T, Kildemoes R . Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials. Clin Pharmacokinet. 2021; 60(10):1335-1348. PMC: 8505367. DOI: 10.1007/s40262-021-01025-x. View

Neumann J, Hussler W, Hofmann B, Gergs U . Contractile Effects of Amphetamine, Pseudoephedrine, Nor-pseudoephedrine (Cathine), and Cathinone on Atrial Preparations of Mice and Humans. J Cardiovasc Pharmacol. 2024; 83(3):243-250. DOI: 10.1097/FJC.0000000000001536. View

Xiao Y, Nikolskaya A, Jaye D, Sigg D . Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway. Cardiovasc Diabetol. 2011; 10:6. PMC: 3037307. DOI: 10.1186/1475-2840-10-6. View

Vila Petroff M, Egan J, Wang X, Sollott S . Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res. 2001; 89(5):445-52. DOI: 10.1161/hh1701.095716. View

Ali S, Ussher J, Baggio L, Kabir M, Charron M, Ilkayeva O . Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Mol Metab. 2015; 4(2):132-43. PMC: 4314543. DOI: 10.1016/j.molmet.2014.11.005. View

McLean B, Wong C, Kabir M, Drucker D . Glucagon-like Peptide-1 receptor Tie2+ cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction. Mol Metab. 2022; 66:101641. PMC: 9706177. DOI: 10.1016/j.molmet.2022.101641. View

Serre V, Dolci W, SCHAERER E, Scrocchi L, Drucker D, Efrat S . Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence. Endocrinology. 1998; 139(11):4448-54. DOI: 10.1210/endo.139.11.6295. View

10.

Kim M, Platt M, Shibasaki T, Quaggin S, Backx P, Seino S . GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013; 19(5):567-75. DOI: 10.1038/nm.3128. View

11.

Neves J, Vasques-Novoa F, Borges-Canha M, Leite A, Sharma A, Carvalho D . Risk of adverse events with liraglutide in heart failure with reduced ejection fraction: A post hoc analysis of the FIGHT trial. Diabetes Obes Metab. 2022; 25(1):189-197. PMC: 9742170. DOI: 10.1111/dom.14862. View

12.

Ban K, Noyan-Ashraf M, Hoefer J, Bolz S, Drucker D, Husain M . Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008; 117(18):2340-50. DOI: 10.1161/CIRCULATIONAHA.107.739938. View

13.

Noyan-Ashraf M, Momen M, Ban K, Sadi A, Zhou Y, Riazi A . GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009; 58(4):975-83. PMC: 2661586. DOI: 10.2337/db08-1193. View

14.

Wu S, Lu W, Chen Z, Dai Y, Chen K, Zhang S . Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized controlled trials. Diabetol Metab Syndr. 2022; 14(1):195. PMC: 9791739. DOI: 10.1186/s13098-022-00970-2. View

15.

Bose A, Mocanu M, Carr R, Brand C, Yellon D . Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2004; 54(1):146-51. DOI: 10.2337/diabetes.54.1.146. View

16.

Neumann J, Boknik P, DePaoli-Roach A, Field L, Rockman H, Kobayashi Y . Targeted overexpression of phospholamban to mouse atrium depresses Ca2+ transport and contractility. J Mol Cell Cardiol. 1998; 30(10):1991-2002. DOI: 10.1006/jmcc.1998.0760. View

17.

Baggio L, Yusta B, Mulvihill E, Cao X, Streutker C, Butany J . GLP-1 Receptor Expression Within the Human Heart. Endocrinology. 2018; 159(4):1570-1584. PMC: 5939638. DOI: 10.1210/en.2018-00004. View

18.

Munch G, Bolck B, Brixius K, Reuter H, Mehlhorn U, Bloch W . SERCA2a activity correlates with the force-frequency relationship in human myocardium. Am J Physiol Heart Circ Physiol. 2000; 278(6):H1924-32. DOI: 10.1152/ajpheart.2000.278.6.H1924. View

19.

Baggio L, Ussher J, McLean B, Cao X, Kabir M, Mulvihill E . The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice. Mol Metab. 2017; 6(11):1339-1349. PMC: 5681270. DOI: 10.1016/j.molmet.2017.08.010. View

20.

Neumann J, Schwarzer D, Fehse C, Schwarz R, Marusakova M, Kirchhefer U . Functional interaction of H-receptors and 5HT-receptors in atrial tissues isolated from double transgenic mice and from human patients. Naunyn Schmiedebergs Arch Pharmacol. 2021; 394(12):2401-2418. PMC: 8592968. DOI: 10.1007/s00210-021-02145-8. View