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(Hypertension. 2007;49:209.)
© 2007 American Heart Association, Inc.

Original Articles

Novel Digitalis-Like Factor, Marinobufotoxin, Isolated From Cultured Y-1 Cells, and Its Hypertensive Effect in Rats

Masamichi Yoshika; Yutaka Komiyama; Motomi Konishi; Toshifumi Akizawa; Takahisa Kobayashi; Mutsuhiro Date; Shinzo Kobatake; Midori Masuda; Hiroya Masaki; Hakuo Takahashi

From the Department of Clinical Sciences and Laboratory Medicine (M.Y., Y.K., M.M., H.M., H.T.), Kansai Medical University, Osaka, Japan; the Department of Analytical Chemistry (M.K., T.A.), Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan; and Diagnostic Research Laboratories (T.K., M.D., S.K.), Wako Pure Chemical Industries Ltd., Hyogo, Japan.

Correspondence to Hakuo Takahashi, Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, Fumizonocho, Moriguchi, Osaka 570-8507, Japan. E-mail takahash{at}hirakata.kmu.ac.jp

Marinobufagenin and telecinobufagin have been identified as digitalis-like factors in mammals. In toads, marinobufagenin-related compounds, such as marinobufotoxin (MBT), have been isolated in some tissues but not in mammals, and its biological action has not been elucidated. Herein, we aimed to explore the possible production and/or secretion of MBT and the biological action in rats. First, the MBT in culture supernatant of the adrenocortical-originated cell line Y-1 was analyzed by high-performance liquid chromatography and sensitive ELISA for marinobufagenin-like immunoreactivity. Moreover, the structural information was obtained by mass spectrometry. To determine the biological action, MBT (9.6 and 0.96 µg/kg per day) was intraperitoneally infused via an osmotic minipump for 1 week. Blood pressure and renal excretion of marinobufagenin-like immunoreactivity were measured. Marinobufagenin-like immunoreactivity was found in Y-1 cell culture media, and the concentration increased until 24 hours. The structural analysis suggested that marinobufagenin-like immunoreactivities were marinobufagenin and MBT, and tandem mass spectrum analysis revealed them with the specific daughter ions. The highest sensitive ELISA-positive peak of marinobufagenin-like immunoreactivity in the media was MBT. Continuous administration of MBT in rats for 1 week significantly increased systolic blood pressure and renal excretion of marinobufagenin-like immunoreactivity compared with control rats (135±3.0 versus 126±2.0 mm Hg and 1.41±0.286 versus 0.34±0.064 ng/day, respectively). These data suggest that MBT, arginine-suberoyl ester of marinobufagenin, can be a novel digitalis-like factor with hypertensive action and is secreted from the adrenocortical cells.

Key Words: marinobufotoxin • digitalis-like factor • adrenal gland • ELISA • mass spectrometry • hypertension

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