Telmisartan, an angiotensin II type 1 receptor antagonist, attenuates T-type Ca2+ channel expression in neonatal rat cardiomyocytes.
Recently, it has been revealed that angiotensin II type 1 receptor (AT(1)) antagonists act as antiarrhythmic agents and that the T-type Ca2+ channel plays an important role in arrhythmia. However, it remains unclear how the T-type Ca2+ channel expression system is involved in angiotensin II-mediated arrhythmogenesis in cardiomyocytes. In this study, we investigated the effect of telmisartan, an AT(1) receptor antagonist, on transcriptional regulation of T-type Ca2+ channel isoform (Ca(v)3.1 and Ca(v)3.2) expression and cardiac contractility using rat neonatal cardiomyocytes. Cultured cardiomyocytes were stimulated with telmisartan and/or angiotensin II for 24 h. T-type Ca2+ currents (I(Ca.T)) were then measured with the patch clamp technique, while Ca(v)3.1 and Ca(v)3.2 mRNA expression were assessed by real-time PCR. Expression of Ca(v)3.1 and Ca(v)3.2 mRNA as well as I(Ca.T) current density in cardiomyocytes increased significantly after long-term application of angiotensin II (24 h), which was accompanied by extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation. In contrast, telmisartan decreased Ca(v)3.1 and Ca(v)3.2 mRNA expression as well as I(Ca.T) in a dose-dependent manner in the absence of angiotensin II. In addition, the basal phosphorylation level of p38MAPK but not ERK1/2 was decreased by telmisartan in the absence of angiotensin II. Valsartan, an AT(1) receptor antagonist, did not mimic the action of telmisartan, while the action of telmisartan was completely blocked by valsartan. These results indicate that telmisartan attenuates T-type Ca2+ channel expression likely through p38MAPK activity in an agonist-independent manner, which suggests a novel pharmacological action of telmisartan.
Morishima
Masaki
M
Department of Pathophysiology, Oita University School of Medicine, Oita 879-5593, Japan. mmoris@med.oita-u.ac.jp
Wang
Yan
Y
Akiyoshi
Yuko
Y
Miyamoto
Shinji
S
Ono
Katsushige
K
D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D044783:F-Box Proteins; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D029961:Zebrafish Proteins; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D020747:Calcium Channels, T-Type; D044783:F-Box Proteins; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D029961:Zebrafish Proteins; C501123:fbxw4 protein, zebrafish; D000804:Angiotensin II; D000068756:Valsartan; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014633:Valine; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077333:Telmisartan