The offset of β-adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline

S. A. Doggrell, C. J. Henderson
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引用次数: 8

Abstract

1 The aim of the study was to test the hypothesis that the offset of action of β-adrenoceptor antagonists on the heart is related to their lipophilicity, with low and highly lipophilic drugs having a rapid and slow offset, respectively. The effects of β-blockers with low (atenolol), moderate (celiprolol), high (propranolol) and very high (bopindolol) lipophilicity on the contractile responses of the rat right ventricle to isoprenaline were determined.

2 Atenolol at 10−−6 and 10−−5m, celiprolol at 10−−7, 10−−6 and 10−−5m, propranolol at 10−−8, 10−−7 and 10−−6m and bopindolol at 2 × 10−−9 and 10−−8m caused parallel rightward shifts of the isoprenaline response curves with no effect on maximum responses. The Schild plots for atenolol, celiprolol and propranolol had slopes that were not significantly different from 1, which is indicative of competitive reversible antagonism. The pKB values were 7.33, 7.78, and 8.79 for atenolol, celiprolol, and propranolol, respectively. The Schild plot for bopindolol had a slope that was significantly greater than 1.

3 Our hypothesis is supported as the effects of propranolol and bopindolol were more slowly offset than those of atenolol and celiprolol. Thus, the concentration-ratio of 141 in the presence of atenolol at 10−−5m was reduced to 4 after the first wash, whereas the ratio of 100 in the presence of propranolol at 10−−7m was only reduced to 45 after a similar wash. The ratio of 54 with celiprolol at 10−−6m was reduced to 5, whereas the ratio of 70 with bopindolol at 10−−8m was only reduced to 28 by the first wash.

4 The effects of bopindolol were very slowly or not reversible over two washes in the absence or presence of atenolol at 10−−6m. It is suggested that bopindolol is a very slowly reversible β-blocker, and that this contributes to its slow offset of action.

β-肾上腺素受体拮抗大鼠右心室对异丙肾上腺素的反应
1本研究的目的是验证β-肾上腺素能受体拮抗剂对心脏作用的抵消与其亲脂性有关的假设,低亲脂性和高亲脂性药物分别具有快速和缓慢的抵消。测定了低(阿替洛尔)、中等(塞利洛尔)、高(心得洛尔)和高(博品多洛尔)亲脂性β受体阻滞剂对大鼠右心室异丙肾上腺素收缩反应的影响。阿替洛尔在10−−6和10−−5 m处,塞利洛尔在10−−7、10−6和10−5 m处,心得洛尔在10−−8、10−7和10−6 m处,bopindolol在2 × 10−9和10−8 m处引起异丙肾上腺素响应曲线平行向右移动,但对最大响应没有影响。阿替洛尔、塞利洛尔和心得洛尔的Schild曲线斜率与1无显著差异,表明它们存在竞争性可逆拮抗作用。阿替洛尔、塞利洛尔和心得安的pKB值分别为7.33、7.78和8.79。bopindolol的Schild曲线斜率显著大于1。我们的假设得到了支持,因为心得安和博品多洛尔的作用比阿替洛尔和塞利洛尔的作用抵消得更慢。因此,在10−−5 m存在阿替洛尔时的浓度比为141,在第一次洗涤后降至4,而在10−−7 m存在普萘洛尔时的浓度比为100,在类似洗涤后仅降至45。54与塞利洛尔在10−−6 m处的比值降至5,而70与bopinddolol在10−−8 m处的比值仅在第一次洗涤时降至28。在10 - 6米不含阿替洛尔或不含阿替洛尔的情况下,bopindolol的作用非常缓慢或不可逆。这表明,bopindolol是一种非常缓慢可逆的β受体阻滞剂,这有助于其缓慢的抵消作用。
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