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 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.
National Research Laboratory for Mitochondrial Signaling Laboratory, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea.
Hyoung Kyu
HK
Kim
Jae Boum
JB
Youm
Sung Ryul
SR
Lee
Se Eun
SE
Lim
Sun-Young
SY
Lee
Tae Hee
TH
Ko
Le Thanh
le T
Long
Bernd
B
Nilius
Du Nam
du N
Won
Jung-Hyun
JH
Noh
Kyung Soo
KS
Ko
Byoung Doo
BD
Rhee
Nari
N
Kim
Jin
J
Han
D000200:Action Potentials / Q000187:drug effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000633:toxicity*; D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity*; D001565:Benzoates / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000077333:Telmisartan; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D019831:Sodium-Calcium Exchanger; D061566:Voltage-Gated Sodium Channels; D012964:Sodium; D019808:Losartan; D002118:Calcium; D000077333:Telmisartan