The receptor occupation and plasma concentration of NKY-722, a water-soluble dihydropyridine-type calcium antagonist, in spontaneously hypertensive rats.
1. The occupation in vivo by NKY-722 of 1,4-dihydropyridine (DHP) calcium antagonist receptors in myocardium, aorta and cerebral cortex was investigated. At 1 and 3 h after oral administration of NKY-722 (3 mg kg-1) in spontaneously hypertensive rats (SHR), there was a significant (44 and 41%, respectively) decrease in the number of myocardial (+)-[3H]-PN 200-110 binding sites (Bmax) compared to control values. A greater reduction of Bmax values was observed at 1 (86%), 3 (88%), 6 (63%) and 12 (46%) h later by a higher dose (10 mg kg-1) of this drug. The occupation of myocardial 1,4-DHP calcium antagonist receptors after oral administration of NKY-722 correlated significantly with its plasma concentration. There was a significant decrease in cerebral cortical (+)-[3H]-PN 200-110 binding (Bmax) at 1 and 3 h after oral administration of NKY-722 (10 mg kg-1). 2. Oral administration of nicardipine (10 mg kg-1) in SHR caused a significant reduction of Bmax values for (+)-[3H]-PN 200-110 binding in myocardium at 1 and 3 h later and in cerebral cortex at 1 h later. 3. The in vivo specific binding of (+)-[3H]-PN 200-110 in particulate fractions of aorta of SHR was significantly (79 and 83%, respectively) reduced at 1 and 6 h after oral administration of NKY-722 (3 mg kg-1), while myocardial (+)-[3H]-PN 200-110 binding was decreased by 52% only at 1 h later. Also, nicardipine administration reduced in vivo ( + )-[3H]-PN 200-110 binding in aorta at 1 and 6 h later and in myocardium at 1 h later. On the other hand, the administration of both NKY-722 and nicardipine had no significant effect on in vivo (+ )-[3H]-PN 200-110 binding in cerebreal cortex.4 It is concluded that NKY-722 may exert more selective and sustained occupation in vivo of 1,4-DHP calcium antagonist receptors in vascular tissues of SHR than in myocardial and brain tissues.
Uchida
S
S
Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Yamada
S
S
Ohkura
T
T
Heshikiri
M
M
Yoshimi
A
A
Shirahase
H
H
Kimura
R
R
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002462:Cell Membrane; D002540:Cerebral Cortex; D004095:Dihydropyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C058351:NKY 722; D009529:Nicardipine