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The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action


Telmisartan is an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma agonist that modulates the renin–angiotensin–aldosterone system. It is used primarily to manage hypertension, diabetic nephropathy, and congestive heart failure. Recent studies have reported that myocardial infarction (MI) has occurred in telmisartan-treated patients. The purpose of the study was to investigate the specific conditions and underlying mechanisms that may result in telmisartan-induced MI. We evaluated the effect of telmisartan on whole hearts, cardiomyocytes, and cardiac sarcolemmal ion channels. Hearts of 8-week-old male Sprague–Dawley rats were perfused with 3, 10, 30, or 100 μM telmisartan or losartan or with normal Tyrode’s solution (control) for 3 h. We found that telmisartan induced myocardial infarction, with an infarct size of 21 % of the total at 30 μM (P < 0.0001) and 63 % of the total area at 100 μM (P < 0.001). Telmisartan also induced cardiac dysfunction (e.g., decreased heart rate, diminished coronary flow, hypercontracture, and arrhythmia). Confocal microscopy demonstrated that 30 μM telmisartan significantly elevated the intracellular Ca2+ level, leading to hypercontracture and cell death. Patch clamp analysis of isolated cardiomyocytes revealed that telmisartan induced Na+ overload by slowing the inactivation of voltage-gated Na+ current (I Na), activating the reverse mode of Na+–Ca2+ exchanger activity, and causing Ca2+ overload. Telmisartan significantly delayed the inactivation of the voltage-gated Na+ channel, causing cytosolic Na+ overload, prolonged action potential duration, and subsequent Ca2+ overload. Above 30 μM, telmisartan may potentially cause cardiac cell death and MI.

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The authors thank Dr. Kyung Im Cho and Seong-Man Kim for valuable discussions and opinions on the manuscript. This study was supported by Priority Research Centers Program and Basic Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2010-0020224, 2012007595, and R13-2007-023-00000-0).

Ethical standards

All experimental procedures were reviewed and approved by the Institutional Review Board of Animals, Inje University College of Medicine. Procedures were performed according to the guidelines of the Institutional Review Board on the ethical use of animals.

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None declared.

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Correspondence to Jin Han.

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Kim, H.K., Youm, J.B., Lee, S.R. et al. The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action. Pflugers Arch - Eur J Physiol 464, 631–643 (2012).

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  • Angiotensin receptor blocker
  • Peroxisome proliferator-activated receptor gamma agonist
  • Cardiac dysfunction
  • Voltage-gated Na+ channel inactivation
  • Na+–Ca2+ exchanger