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.