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