Yamada Shizuo, Nakajima Mariko, Kusaka Toyofumi, Uchida Shinya, Kimura Ryohei
Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Life Sci. 2002 Mar 15;70(17):1999-2011. doi: 10.1016/s0024-3205(01)01541-7.
The present study was undertaken to characterize the in vivo 1,4-dihydropyridine (DHP) receptor binding of long-acting 1,4-DHP calcium channel antagonists in the mesenteric artery and other tissues of SHR. In vivo specific binding of (+)-[3H]PN 200-110 in the SHR mesenteric artery was significantly (36.6-49.7 %) reduced 1-8 h after oral administration of benidipine (1.84 micromol/kg). A greater reduction in (+)-[3H]PN 200-110 binding in the mesenteric artery was observed at a higher dose (5.53 micromol/kg) of this drug. This dose of benidipine also reduced significantly the in vivo specific (+)-[3H]PN 200-110 binding in the aorta but not in the myocardium and cerebral cortex. Following oral administration of amlodipine (17.6 micromol/kg), a significant (51.7-94.2 %) reduction in (+)-[3H]PN 200-110 binding was seen at 1-18 h in the mesenteric artery and at 1-12 h in the aorta. Only a slight reduction in myocardial and cerebral cortical (+)-[3H]PN 200-110 binding was seen following amlodipine administration. In contrast, oral administration of nifedipine (28.9 micromol/kg) reduced markedly in vivo (+)-[3H]PN 200-110 binding in all the tissues of SHR at 1-6 h, and the degree and time-course of the reduction did not differ significantly among the tissues. The area under the curve (AUC) for the receptor occupancy vs time was calculated from the reduction rate (%) of in vivo specific (+)-[3H]PN 200-110 binding. The ratios of the AUCmesenteric artery to AUCaorta or AUCmesenteric artery to AUCmyocardium after oral administration of benidipine and amlodipine were greater than the corresponding value for nifedipine. The degree and time-course of arterial receptor occupancy by benidipine and amlodipine agreed well with those of their hypotensive effects in the conscious SHR. In conclusion, the present study demonstrates that benidipine and amlodipine may occupy, in a more selective and sustained manner, 1,4-DHP receptors in arterial tissues than in other tissues of SHR, and thus, such receptor binding specificity may be responsible for the long-lasting hypotensive effects of these drugs.
本研究旨在表征长效1,4 - 二氢吡啶（DHP）钙通道拮抗剂在自发性高血压大鼠（SHR）肠系膜动脉及其他组织中的体内1,4 - 二氢吡啶（DHP）受体结合情况。口服贝尼地平（1.84微摩尔/千克）后1 - 8小时，SHR肠系膜动脉中（+） - [³H] PN 200 - 110的体内特异性结合显著降低（36.6 - 49.7%）。给予该药物更高剂量（5.53微摩尔/千克）时，肠系膜动脉中（+） - [³H] PN 200 - 110结合的降低更为明显。该剂量的贝尼地平也显著降低了主动脉中（+） - [³H] PN 200 - 110的体内特异性结合，但对心肌和大脑皮层无影响。口服氨氯地平（17.6微摩尔/千克）后，肠系膜动脉在1 - 18小时以及主动脉在1 - 12小时，（+） - [³H] PN 200 - 110结合显著降低（51.7 - 94.2%）。氨氯地平给药后，心肌和大脑皮层中（+） - [³H] PN 200 - 110结合仅有轻微降低。相比之下，口服硝苯地平（28.9微摩尔/千克）在1 - 6小时显著降低了SHR所有组织中（+） - [³H] PN 200 - 110的体内结合，且各组织中结合降低的程度和时间进程无显著差异。根据体内特异性（+） - [³H] PN 200 - 110结合的降低率（%）计算受体占有率随时间变化的曲线下面积（AUC）。口服贝尼地平和氨氯地平后，肠系膜动脉与主动脉或肠系膜动脉与心肌的AUC比值大于硝苯地平的相应值。贝尼地平和氨氯地平对动脉受体的占有率及其时间进程与其在清醒SHR中的降压作用一致。总之，本研究表明，与SHR的其他组织相比，贝尼地平和氨氯地平可能以更具选择性和持续性的方式占据动脉组织中的1,4 - DHP受体，因此，这种受体结合特异性可能是这些药物长效降压作用的原因。
