Hamra M, Danilo P, Rosen M R
Division of Developmental Pharmacology, College of Physicians and Surgeons of Columbia University, New York, N.Y.
Dev Pharmacol Ther. 1988;11(3):155-65. doi: 10.1159/000457683.
We used standard microelectrode techniques to determine developmental differences in the direct membrane and beta-blocking effects of nadolol on the electrophysiologic properties of adult and neonatal canine Purkinje fibers (PF). To study direct membrane effects, we superfused PF with nadolol 1 X 10(-8)-1 X 10(-4) M while stimulating them at a BCL of 800 ms. Nadolol less than 1 X 10(-5) M had no effect on the transmembrane potential in either age group. Nadolol, greater than or equal to 1 X 10(-5) M, increased action potential duration at 100% repolarization (APD100) in adult fibers and nadolol, 1 X 10(-4) M, decreased Vmax and APD at 50% repolarization (APD50) in neonatal fibers (p less than 0.05). The beta-blocking effects of nadolol were studied by examining the chronotropic response in automatic PF to cumulative doses of l-isoproterenol.HCl 3 X 10(-10)-3 X 10(-6) M, alone and then in the continued presence of nadolol 5 X 10(-8)-5 X 10(-6) M. Nadolol caused a concentration-dependent shift to the right of the concentration-response curve in both age groups. pA2 determinations in adult (7.88) and neonatal (7.57) PF indicated that there was no developmental difference in the affinity of nadolol for the beta-receptor (p greater than 0.05). Our results indicate that nadolol shows developmental changes in its direct membrane effects but not its beta-blocking effects. The latter characteristic differs from that of the more highly lipid-soluble beta-blocker, propranolol. This suggests that different beta-blocking molecules have differing abilities to block the beta-receptor at different ages that are influenced importantly by their lipid solubility.
我们采用标准微电极技术，来确定纳多洛尔对成年和新生犬浦肯野纤维（PF）电生理特性的直接膜效应和β受体阻断效应的发育差异。为研究直接膜效应，我们用1×10⁻⁸ - 1×10⁻⁴M的纳多洛尔灌注PF，同时以800毫秒的基础周期长度（BCL）对其进行刺激。低于1×10⁻⁵M的纳多洛尔对两个年龄组的跨膜电位均无影响。大于或等于1×10⁻⁵M的纳多洛尔可增加成年纤维在100%复极化时的动作电位时程（APD100），而1×10⁻⁴M的纳多洛尔可降低新生纤维在50%复极化时的最大上升速率（Vmax）和动作电位时程（APD50）（P<0.05）。通过检测自律性PF对累积剂量的l-异丙肾上腺素盐酸盐3×10⁻¹⁰ - 3×10⁻⁶M的变时反应，来研究纳多洛尔的β受体阻断效应，先是单独检测，然后在持续存在5×10⁻⁸ - 5×10⁻⁶M纳多洛尔的情况下检测。纳多洛尔在两个年龄组均引起浓度反应曲线浓度依赖性右移。成年（7.88）和新生（7.57）PF的pA2测定表明，纳多洛尔对β受体的亲和力无发育差异（P>0.05）。我们的结果表明，纳多洛尔的直接膜效应存在发育变化，但其β受体阻断效应无发育变化。后一特性与脂溶性更高的β受体阻断剂普萘洛尔不同。这表明不同的β受体阻断分子在不同年龄阻断β受体的能力不同，这受到其脂溶性的重要影响。
