Koichi Nakayama1, Yoshihisa Fukuta1, Akihiko Kiyoshi1,
Yoshiyuki Iwatsuki1, Kunio Ishii1, Tomohisa Ishikawa1,
Mari Iida2, Hijiri Iwata2 and Makoto Enomoto2
1Department of Pharmacology, Faculty of Pharmaceutical Sciences,
University of Shizuoka,
52 - 1 Yada, Shizuoka City, Shizuoka 422 - 8526, Japan
2Biosafety Research Center, Foods, Drugs and Pesticides, 582
- 2 Arahama, Shioshinden, Fukude, Iwata, Shizuoka 437 - 1312, Japan
Abstract: We examined the binding of a 1,4-dihydropyridine-sensitive
Ca2+ channel ligand, (+)[3H]isradipine (PN200-110),
and that of an ATP-sensitive K+ (KATP) channel ligand, [3H]glyburide,
to heart, lung and brain membranes isolated from Sprague-Dawley rats made
pulmonary hypertensive by monocrotaline, a pyrrolizidine alkaloid. A single
subcutaneous injection of monocrotaline increased right ventricular systolic
pressure, a measure of pulmonary arterial pressure, and the thickness of
the right ventricular free wall in 3 to 4 weeks. The (+)-[3H]PN200-110
and [3H]glyburide binding site densities (Bmax) were
reduced in hypertrophied right ventricles when normalized per unit protein
in comparison with those of age-matched control (sham) rats, whereas the
values of the dissociation constant (Kd) of both ligands bound to the
hypertrophied right ventricle were not significantly changed. The [3H]PN200-110
binding to the lung membranes of the monocrotaline-induced pulmonary hypertensive
rats was increased. The results indicate that the change in the binding
of 1,4-dihydropyridine Ca2+ and KATP channel ligands
to heart membranes may contribute to the pathological alteration of cardiopulmonary
structure and functions in rats with pulmonary hypertension induced by monocrotaline.
Keywords: Ca2+ channel, ATP-sensitive K+ channel,
Monocrotaline, Pulmonary hypertension, Binding assay