Hempel A, Noll T, Bach C, Piper H M, Willenbrock R, Höhnel K, Haller H, Luft F C
Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medizinische Fakultät der Charité, Humboldt University of Berlin, 13122 Berlin, Germany.
Am J Physiol. 1998 Nov;275(5):H1818-25. doi: 10.1152/ajpheart.1998.275.5.H1818.
The atrial natriuretic peptide (ANP)-C receptor is generally believed to clear ANP; however, the ANP-C receptor may serve to reduce cAMP by inhibiting adenylate cyclase. ANP decreases endothelial permeability in coronary endothelial cell monolayers. We tested the hypothesis that part of this effect might be mediated by the ANP-C receptor. We used an endothelial cell monolayer from rat coronary endothelium and measured albumin flux. We applied either ANP or a ring-deleted ANP (C-ANP), which only stimulates the ANP-C receptor. ANP and C-ANP both decreased permeability from 100 pM to 100 nM by 60 and 30%, respectively. ANP increased endothelial cGMP contents 5.5-fold, whereas C-ANP had no effect. ANP reduced endothelial cAMP contents by 75%, which was only partly blocked by pertussis toxin. C-ANP also reduced cAMP; however, this effect was completely blocked by pertussis toxin. Protein kinase G inhibition blocked the ANP-mediated decrease in permeability by 50%. In contrast, pretreatment with pertussis toxin, in the face of protein kinase G inhibition, blocked the effect completely. C-ANP decreased permeability by half the amount of ANP. This C-ANP effect was completely blocked by pertussis toxin but not by protein kinase G inhibition. Isoproterenol (10 microM) increased permeability by almost 50%, which was completely blocked by ANP but only partially blocked by C-ANP. The C-ANP effect was blocked completely by pertussis toxin. Isoproterenol increased cAMP threefold, which was abolished by ANP. C-ANP reduced the isoproterenol-induced increase in cAMP by 50%. Isoproterenol had no effect on cGMP. We conclude that agonist binding to the ANP-C receptor inhibits cAMP production via a Gi protein-coupled signaling system. This inhibition may contribute to the decreased endothelial permeability evoked by ANP in this system.
心房利钠肽（ANP）-C受体通常被认为可清除ANP；然而，ANP-C受体可能通过抑制腺苷酸环化酶来降低环磷酸腺苷（cAMP）水平。ANP可降低冠状动脉内皮细胞单层的内皮通透性。我们检验了这样一个假说，即这种效应的一部分可能由ANP-C受体介导。我们使用了来自大鼠冠状动脉内皮的内皮细胞单层，并测量了白蛋白通量。我们应用了ANP或一种环缺失的ANP（C-ANP），后者仅刺激ANP-C受体。ANP和C-ANP分别使通透性从每升100皮摩尔（pM）降至每升100纳摩尔（nM）时降低了60%和30%。ANP使内皮细胞中环鸟苷酸（cGMP）含量增加了5.5倍，而C-ANP则无此作用。ANP使内皮细胞中cAMP含量降低了75%，百日咳毒素仅部分阻断了这一作用。C-ANP也降低了cAMP；然而，这一效应被百日咳毒素完全阻断。蛋白激酶G抑制可阻断ANP介导的通透性降低的50%。相反，在存在蛋白激酶G抑制的情况下，用百日咳毒素预处理可完全阻断该效应。C-ANP使通透性降低的幅度为ANP的一半。C-ANP的这种效应被百日咳毒素完全阻断，但未被蛋白激酶G抑制所阻断。异丙肾上腺素（10微摩尔/升）使通透性增加了近50%，这被ANP完全阻断，但仅被C-ANP部分阻断。C-ANP的效应被百日咳毒素完全阻断。异丙肾上腺素使cAMP增加了三倍，这被ANP消除。C-ANP使异丙肾上腺素诱导的cAMP增加降低了50%。异丙肾上腺素对cGMP无影响。我们得出结论，激动剂与ANP-C受体结合通过Gi蛋白偶联信号系统抑制cAMP产生。这种抑制可能有助于该系统中ANP引起的内皮通透性降低。
