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- Title
The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action.
- Authors
Kim, Hyoung Kyu; Youm, Jae Boum; Lee, Sung Ryul; Lim, Se Eun; Lee, Sun-Young; Ko, Tae Hee; Long, Le Thanh; Nilius, Bernd; Won, Du Nam; Noh, Jung-Hyun; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Han, Jin
- Abstract
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 Ca(2+) 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(+)-Ca(2+) exchanger activity, and causing Ca(2+) overload. Telmisartan significantly delayed the inactivation of the voltage-gated Na(+) channel, causing cytosolic Na(+) overload, prolonged action potential duration, and subsequent Ca(2+) overload. Above 30 μM, telmisartan may potentially cause cardiac cell death and MI.
- Publication
Pflugers Archiv : European journal of physiology, 2012, Vol 464, Issue 6, p631
- ISSN
1432-2013
- Publication type
Journal Article
- DOI
10.1007/s00424-012-1170-3