Yamada S, Uchida S, Urayama A, Kimura R
Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Pharmacology. 1999 Oct;59(4):171-82. doi: 10.1159/000028318.
The occupancy of 1,4-dihydropyridine (DHP) receptors by pranidipine was characterized in tissues of spontaneously hypertensive rats (SHR). Oral administration of pranidipine (1 and 3 mg/kg) in SHR produced significant (26-67%) decreases in the number of specific (+)-[(3)H]PN 200-110 binding sites (B(max)) with 2- to 4-fold increases in the apparent dissociation constant (K(d)) in myocardial tissues at 1, 3 and 6 h later. In these rats, there was a reduction (16-37%) of B(max) in cerebral cortical (+)-[(3)H]PN 200-110 binding. Occupancy of myocardial DHP receptors after oral administration of pranidipine correlated well with its plasma concentration. Oral administration of nifedipine (10 mg/kg) in SHR caused significant increase in K(d) values for (+)-[(3)H]PN 200-110 binding in myocardium and cerebral cortex at 1 h later. In vivo specific (+)-[(3)H]PN 200-110 binding in particulate fractions of SHR aorta was markedly (59-78%) reduced at 1, 3 and 12 h after oral administration of pranidipine (3 mg/kg), while myocardial (+)-[(3)H]PN 200-110 binding was decreased by 46-48% at 1 and 3 h later. In these rats, there was a significant decrease (34%) in cerebral cortical (+)-[(3)H]PN 200-110 binding at 3 h later. In contrast, nifedipine administration produced a similar degree of reduction (71-84%) of in vivo (+)-[(3)H]PN 200-110 binding in the myocardium, aorta and cerebral cortex. It is concluded that pranidipine may exert more selective and sustained occupation in vivo of DHP receptors in vascular tissues of SHR than in myocardial and brain tissues.
在自发性高血压大鼠（SHR）组织中对普拉地平占据1,4 - 二氢吡啶（DHP）受体的情况进行了表征。给SHR口服普拉地平（1和3mg/kg）后，1、3和6小时后心肌组织中特异性（+）-[(3)H]PN 200 - 110结合位点数量（B(max)）显著降低（26 - 67%），表观解离常数（K(d)）增加2至4倍。在这些大鼠中，大脑皮质（+）-[(3)H]PN 200 - 110结合的B(max)降低了（16 - 37%）。口服普拉地平后心肌DHP受体的占据情况与其血浆浓度密切相关。给SHR口服硝苯地平（10mg/kg）1小时后，心肌和大脑皮质中（+）-[(3)H]PN 200 - 110结合的K(d)值显著增加。口服普拉地平（3mg/kg）后1、3和12小时，SHR主动脉微粒体部分的体内特异性（+）-[(3)H]PN 200 - 110结合显著降低（59 - 78%），而1和3小时后心肌（+）-[(3)H]PN 200 - 110结合降低了46 - 48%。在这些大鼠中，3小时后大脑皮质（+）-[(3)H]PN 200 - 110结合显著降低（34%）。相比之下，给予硝苯地平在心肌、主动脉和大脑皮质中使体内（+）-[(3)H]PN 200 - 110结合降低了相似程度（71 - 84%）。得出的结论是，与心肌和脑组织相比，普拉地平在体内对SHR血管组织中的DHP受体可能具有更具选择性和持续性的占据作用。
