Reinduction of T-type calcium channels by endothelin-1 in failing hearts in vivo and in adult rat ventricular myocytes in vitro.
BACKGROUND
In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated.


RESULTS
We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in alpha-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (-0.87+/-0.18 pA/pF at -30 mV, P<0.01 versus LVH). This was associated with a significant increase in the alpha-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of alpha-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats.


CONCLUSIONS
ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.
Izumi
Toshiaki
T
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Kihara
Yasuki
Y
Sarai
Nobuaki
N
Yoneda
Takeshi
T
Iwanaga
Yoshitaka
Y
Inagaki
Koichi
K
Onozawa
Yoko
Y
Takenaka
Hiroyuki
H
Kita
Toru
T
Noma
Akinori
A
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology
D000959:Antihypertensive Agents; D020747:Calcium Channels, T-Type; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D000804:Angiotensin II; D000077300:Bosentan