Journal
PHARMACEUTICALS
Volume 15, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/ph15091055
Keywords
rosiglitazone; hidden cardiotoxicity; ischemic preconditioning; I/R injury model; diabetes; thiazolidinedione; simulated ischemia; reperfusion; Avandia
Categories
Funding
- National Research, Development and Innovation Office of Hungary (NKFIA) [NVKP-16-1-2016-0017]
- National Research, Development and Innovation Office of Hungary (NKFIH) [K139237]
- Thematic Excellence Program of the Ministry for Innovation and Technology in Hungary, within the Semmelweis University [2020-4.1.1.-TKP2020]
- National Heart Laboratory Program [RRF2.3.1-21-2022-00003]
- National Research, Development and Innovation Fund
- Semmelweis 250+ Excellence PhD Scholarship [EFOP-3.6.3-VEKOP-16-2017-00009]
- Gedeon Richter Excellence PhD Scholarship
- New National Excellence Program of the Ministry for Innovation and Technology [UNKP-21-4-I-60]
- [VEKOP-2.3.3-15-2017-00016]
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The chronic administration of rosiglitazone does not have significant hidden cardiotoxic effects in myocardial ischemia/reperfusion injury models. However, it may inhibit the antiarrhythmic effects of ischemic preconditioning, which requires further exploration.
Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 mu M. At 0.1 and 0.3 mu M, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.
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