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muscles was approximately 1 g and was kept constant throughout
the experiments. Under these conditions, the right atria were al-
lowed to equilibrate for 60 min with exchange of bath solution
every 20 min before drug administration. Amplitude of constric-
tion was measured isometrically using a force–displacement trans-
ducer (Nihon Kohden SB-1T) to obtain the spontaneous beat rate
with a tachometer (Nihon Kohden AT-600G) that was triggered
by the contractile pulse. After the initial spontaneous beat rate
was recorded, test compounds dissolved in DMSO and diluted with
saline to the desired concentration were added to the bath solution
cumulatively at 30-min intervals to construct a concentration–re-
sponse curve. The EC30 value for the concentration of the com-
pounds producing a 30% reduction from initial spontaneous beat
rate was determined via linear regression.
5.2.3. Pharmacology in vivo study (po)
Male SHR rats (300–350 g) were anesthetized with pentobarbi-
tal (60 mg/kg ip), and a polyethylene cannula (PE-50) was im-
planted in the common carotid artery with the opposite end of
the catheter then routed to an exit site at the back of the neck. Ani-
mals were allowed a one- to two-day recovery period after the
operation, during which time they were housed individually with
free access to rat chow and water. Blood pressure was measured
using a pressure transducer (Nihon Kohden DX-100) coupled to
the carotid artery cannula and a pressure amplifier (Nihon Kohden
AP-621G) and was continuously recorded using a polygraph sys-
tem. Heart rate was measured with a cardiotachometer (Nihon
Kohden AT-600G) triggered by the blood pressure pulsewave. After
a 30-min measurement period to establish baseline values, test
compounds were orally administrated as an aqueous solution by
gavage at 10 and 30 mg/kg (salt form).
Acknowledgements
We thank Dr. Fukushi Hirayama for his helpful support in pre-
paring this manuscript. We are also grateful to Dr. Hironori Harada,
Dr. Masakazu Imamura, and Mr. Kyoichi Maeno for their useful ad-
vice. Finally, we wish to thank Mr. Kazuhiko Mizukami, Miss Yur-
iko Komiya, Dr. Noriyasu Kanie, Mr. Satoshi Konagai, and Mr.
Eisaku Yamamoto for performing the biological experiments, and
the members of the Division of Analytical Science Laboratories
for elemental analysis and spectral measurements.
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