Published Online
on October 27, 2003

A more recent version of this article appeared on November 18, 2003

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Submitted on June 16, 2002
Revised on July 15, 2003
Accepted on July 16, 2003

Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

Toshiaki Izumi MD, Yasuki Kihara MD, PhD^*, Nobuaki Sarai MD, Takeshi Yoneda MD, Yoshitaka Iwanaga MD, PhD, Koichi Inagaki MD, PhD, Yoko Onozawa MD, Hiroyuki Takenaka MD, Toru Kita MD, PhD, and Akinori Noma MD, PhD

From the Department of Cardiovascular Medicine (T.I., Y.K., T.Y., Y.I., K.I., Y.O., H.T., T.K.) and the Department of Molecular Biophysics (N.S., A.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan.

^* To whom correspondence should be addressed. E-mail: kihara{at}kuhp.kyoto-u.ac.jp.

Background--In ventricular myocardium, the T-type Ca²⁺ current (I_Ca,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.

Methods and 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 I_Ca,T (measured in the freshly isolated LV myocytes) nor an increase in -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, I_Ca,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 -1G mRNA level. The chronic bosentan treatment eliminated both the elevation of -1G mRNA level and I_Ca,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 I_Ca,T in normal adult myocytes in culture from Sprague-Dawley rats.

Conclusions--I_Ca,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

Key words: hypertrophy • heart failure • calcium • endothelin • angiotensin II

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