Grenz A, Klein J, Köhle C, Freudenthaler S, Proksch B, Wu J, Wolf S, Osswald H, Gleiter C H
Department of Pharmacology and Experimental Therapy, Institute of Pharmacology and Toxicology, University Hospital of Tübingen, Otfried-Müller-Strasse 45, 72076 Tübingen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2006 Aug;373(5):342-8. doi: 10.1007/s00210-006-0085-y. Epub 2006 Jul 29.
It has been hypothesized that autacoids, such as endothelin-1 (ET), may modulate erythropoietin (Epo) secretion. Therefore, we studied the effect of ET-1 infusion and of a nonselective ET(A/B) receptor antagonist on Epo secretion under carbon monoxide (CO) exposure. Anesthetized rats were supplied with room temperature air containing increasing concentrations of CO by an aerating cap. A CO-Epo dose-response curve over the range of 0.02-0.14 vol% CO was conducted. Subpressor doses of ET-1 (3 pmol/min/kg BW) and the ET(A/B) receptor antagonist LU302872 (LU; 30 mg/kg) were applied to anaesthetized rats under normoxia (controls CON, ET, LU) and following hypoxia (CO exposure; H-CON, H-ET, H-LU). Mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), Epo and ET-1 serum concentrations (ELISA) and renal Epo mRNA (Light Cycler) were determined. The EC50 value for CO was 0.1 vol% with a 70-fold increase in Epo serum concentrations. CO exposure increased Epo serum and Epo mRNA concentrations in the expected range in all groups. None of the treatments with ET or LU influenced the effect of hypoxia on Epo serum concentrations and renal Epo mRNA content. Under hypoxia, administration of ET-1 as well as LU prevented the hypoxia-induced decrease in MAP (p<0.05). Under hypoxia, GFR was reduced by 50% except for H-LU with values comparable to normoxia. Taken together, the influence of hypoxia exceeds by far the effect of ET-1 on Epo production, irrespective of the presence or absence of exogenous ET-1. Thus, ET-1 does not appear to be a major modulator of Epo production.
据推测，自分泌调节因子，如内皮素-1（ET），可能会调节促红细胞生成素（Epo）的分泌。因此，我们研究了在一氧化碳（CO）暴露情况下，ET-1输注以及非选择性ET（A/B）受体拮抗剂对Epo分泌的影响。通过通气帽向麻醉大鼠供应含氧量不断增加的室温空气。绘制了0.02-0.14体积% CO范围内的CO-Epo剂量反应曲线。在常氧（对照组CON、ET、LU）以及低氧（CO暴露；H-CON、H-ET、H-LU）条件下，将亚升压剂量的ET-1（3 pmol/分钟/千克体重）和ET（A/B）受体拮抗剂LU302872（LU；30毫克/千克）应用于麻醉大鼠。测定平均动脉血压（MAP）、肾小球滤过率（GFR，菊粉清除率）、Epo和ET-1血清浓度（酶联免疫吸附测定）以及肾脏Epo mRNA（Light Cycler）。CO的半数有效浓度（EC50）值为0.1体积%，Epo血清浓度增加了70倍。CO暴露使所有组的Epo血清和Epo mRNA浓度在预期范围内增加。ET或LU的任何处理均未影响低氧对Epo血清浓度和肾脏Epo mRNA含量的作用。在低氧条件下，给予ET-1以及LU可防止低氧诱导的MAP降低（p<0.05）。在低氧条件下，除H-LU组外，GFR降低了50%，其值与常氧相当。综上所述，无论是否存在外源性ET-1，低氧的影响远远超过ET-1对Epo产生的影响。因此，ET-1似乎不是Epo产生的主要调节因子。
