Am. J. Respir. Cell Mol. Biol., Volume 23, Number 2, August, 2000 213-221

Endothelin-1 Is a Potent Activator of Nonselective Cation Currents in Human Bronchial Smooth Muscle Cells

Hitoshi Oonuma, Toshiaki Nakajima, Taiji Nagata, Kuniaki Iwasawa, Yuepeng Wang, Hisanori Hazama, Yutaka Morita, Yue Wang, Kazuhiko Yamamoto, Ryozo Nagai, and Masao Omata

Departments of Respiratory Medicine, Cardiovascular Medicine, and Gastroenterology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan

The effects of endothelin (ET)-1 on cultured human bronchial smooth muscle cells (HBSMC) were investigated and compared with those of histamine, using the patch clamp techniques and measurements of intracellular Ca²⁺ ([Ca²⁺]_i). Both ET-1 and histamine caused an initial transient elevation of [Ca²⁺]_i by Ca²⁺ mobilization, followed by a sustained rise due to Ca²⁺ entry. Nicardipine inhibited the sustained phase, but La³⁺ abolished it. With low ethyleneglycol-bis-(-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) and K⁺ internal solutions, both ET-1 and histamine induced a sustained depolarization from approximately 40 to 20 mV. Under voltage clamp conditions, both drugs transiently activated an outward K⁺ current at a holding potential of 0 mV. Additionally, with a Cs⁺ internal solution, they elicited another transient inward current, frequently followed by current oscillations. These transient currents were blocked by high EGTA or heparin. With high EGTA and Cs⁺ internal solutions, both drugs activated a long-lasting inward current. The reversal potential of these agonist-induced currents was approximately 0 mV and was not altered by the replacement of internal or external concentration of Cl, suggesting that the inward current was a nonselective cation current (I_cat). The half-maximal effective concentration to activate I_cat was 12 nM for ET-1 and 11 µM for histamine. La³⁺ and Cd²⁺ abolished these agonist-induced I_cat. The effects of ET-1 on [Ca²⁺]_i and I_cat could be blocked by combined pretreatment with BQ-123 and BQ-788. Sarafotoxin S6c also increased [Ca²⁺]_i and activated I_cat. By polymerase chain reaction of reverse transcribed RNA, we detected both ET-A and ET-B receptor messenger RNA. These results provide the first evidence that ET-1 is a potent activator of I_cat in HBSMC via ET-A and ET-B receptors, and the activation of I_cat plays an important role in ET-1-induced Ca²⁺ entry in human airways.

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