Angeles D M, Williams J, Purdy R E, Zhang L, Pearce W J
Center for Perinatal Biology, Department of Physiology, Loma Linda University School of Medicine, Loma Linda, California 92350, USA.
Am J Physiol Regul Integr Comp Physiol. 2001 Feb;280(2):R410-7. doi: 10.1152/ajpregu.2001.280.2.R410.
Whereas previous studies have established that many mechanisms mediating pharmacomechanical coupling are subject to regulation, evidence of physiological regulation of the coupling efficiency between receptor activation and second-messenger production is scarce. The present studies address the hypothesis that acute hypoxia and maturation can influence the mass of second-messenger production for each activated agonist-bound receptor ("receptor gain"). For this assessment, receptor density and agonist affinity values were used to calculate 5-hydroxytryptamine (5-HT) concentrations that would produce standardized numbers of bound receptors (8.5 fmol/mg protein) in each experimental group and thus minimize effects of age or hypoxia on receptor density or agonist affinity. After 3 min of exposure to these 5-HT concentrations, normoxic magnitudes of contraction were similar (as %potassium maxima) in fetal (50 +/- 14%) and adult (40 +/- 9%) arteries, but hypoxia (PO(2) approximately 9--12 Torr for 30 min) depressed contractile tensions with a significantly different time course and magnitude in fetal (30 +/- 10%) and adult (17 +/- 11%) arteries (P < 0.05). Basal inositol 1,4,5-trisphosphate (IP(3)) values (in pmol/mg protein) were significantly greater in fetal (94 +/- 16) than in adult (44 +/- 6) arteries, and integrated areas above baseline for the IP(3) time courses (in nmol-s/mg protein) were significantly greater in fetal than in adult arteries both in normoxic (14.3 +/- 1.8 vs. 9.1 +/- 1.6) and hypoxic (15.0 +/- 2.1 vs. 8.6 +/- 1.2) conditions (P < 0.05). Hypoxia altered the IP(3) time courses both in the fetus and the adult but had no significant effect on IP(3 )mobilization or receptor gain. These data demonstrate that for the 5-HT(2a) receptor predominant in this preparation, receptor gain can be experimentally determined, is not influenced by acute hypoxia, but is greater in fetal than in adult ovine carotid arteries.
尽管先前的研究已经证实，许多介导药物机械偶联的机制都受到调控，但关于受体激活与第二信使产生之间偶联效率的生理调节证据却很少。本研究探讨了急性缺氧和成熟是否会影响每个被激活的激动剂结合受体产生的第二信使量（“受体增益”）这一假说。为了进行此项评估，受体密度和激动剂亲和力值被用于计算在每个实验组中能产生标准化数量结合受体（8.5 fmol/mg蛋白质）的5-羟色胺（5-HT）浓度，从而将年龄或缺氧对受体密度或激动剂亲和力的影响降至最低。在暴露于这些5-HT浓度3分钟后，胎儿（50±14%）和成年（40±9%）动脉的常氧收缩幅度相似（以钾最大收缩幅度的百分比表示），但缺氧（PO₂约9 - 12 Torr，持续30分钟）会降低收缩张力，且在胎儿（30±10%）和成年（17±11%）动脉中的时间进程和幅度有显著差异（P < 0.05）。胎儿动脉中基础肌醇1,4,5-三磷酸（IP₃）值（以pmol/mg蛋白质计）显著高于成年（94±16 vs. 44±6）动脉，并且在常氧（14.3±1.8 vs. 9.1±1.6）和缺氧（15.0±2.1 vs. 8.6±1.2）条件下，胎儿动脉中IP₃时间进程高于基线的积分面积（以nmol·s/mg蛋白质计）也显著高于成年动脉（P < 0.05）。缺氧改变了胎儿和成年动物的IP₃时间进程，但对IP₃动员或受体增益没有显著影响。这些数据表明，对于该制剂中占主导地位的5-HT₂a受体，受体增益可以通过实验确定，不受急性缺氧影响，但在胎儿绵羊颈动脉中比成年动物更大。
