Bedarida G, Bushell E, Blaschke T F, Hoffman B B
Division of Clinical Pharmacology, Stanford University Medical Center, CA 94305-5113, USA.
Clin Pharmacol Ther. 1995 Jul;58(1):73-80. doi: 10.1016/0009-9236(95)90074-8.
Aging is associated with alterations in the responses to several important vasoactive drugs. We have investigated histamine-mediated venodilation across the adult age range using the human hand vein compliance technique. Histamine produces dilation in human veins by activating both H1- and H2-receptors.
Full dose-response curves to histamine were constructed in 16 healthy volunteers (mean age, 47 +/- 20 years; age range, 21 to 80 years) by infusing histamine (2 to 136 ng/min) into dorsal hand veins preconstricted with the alpha-adrenergic selective agonist phenylephrine.
Histamine was an efficacious venodilator across the age range; the average maximal response (Emax) was 122 +/- 45% and the geometric mean ED50 (the dose producing half-maximal response) was 16.6 ng/min for all subjects. Dose-response curves to histamine were repeated after infusion of the H2-selective antagonist cimetidine at a dose sufficient to completely block the H2-mediated response (49 micrograms/min). Cimetidine did not inhibit the Emax in the elderly as much as it did in the young subjects. The Emax to histamine in the presence of cimetidine plotted against age showed a significant relationship (r = 0.62, p = 0.02).
These results suggest that, although the overall histamine-induced venodilation is conserved in aging, there is a loss of the signal transduction pathway activated by way of H2-receptors but no loss in function of H1-receptors. Consequently, these results suggest differential changes in function of H1- versus H2-histamine receptors with aging. Because H1-receptors are coupled to endothelial-derived relaxing factor release and because H2-receptors activate cyclic adenosine monophosphate in smooth muscle, the results are compatible with hypothesis that there are specific changes in these signal transduction pathways with aging.
衰老与对几种重要血管活性药物的反应改变有关。我们使用人手部静脉顺应性技术研究了成年各年龄段组胺介导的静脉扩张。组胺通过激活H1和H2受体使人静脉扩张。
对16名健康志愿者（平均年龄47±20岁；年龄范围21至80岁），通过向预先用α-肾上腺素能选择性激动剂去氧肾上腺素收缩的手背静脉输注组胺（2至136 ng/min），构建组胺的完整剂量-反应曲线。
组胺在各年龄段均为有效的静脉扩张剂；所有受试者的平均最大反应（Emax）为122±45%，几何平均ED50（产生半数最大反应的剂量）为16.6 ng/min。在输注足以完全阻断H2介导反应的剂量（49μg/min）的H2选择性拮抗剂西咪替丁后，重复组胺的剂量-反应曲线。西咪替丁对老年人Emax的抑制作用不如对年轻受试者的抑制作用明显。存在西咪替丁时组胺的Emax与年龄作图显示出显著相关性（r = 0.62，p = 0.02）。
这些结果表明，尽管衰老过程中组胺诱导的总体静脉扩张作用保持不变，但通过H2受体激活的信号转导途径有所丧失，而H1受体功能未丧失。因此，这些结果提示衰老过程中H1与H2组胺受体功能存在差异变化。由于H1受体与内皮源性舒张因子释放相关联，且H2受体在平滑肌中激活环磷酸腺苷，这些结果与衰老过程中这些信号转导途径存在特定变化的假说相符。
