Gauthier Kathryn M, Zhang David X, Cui Lijie, Nithipatikom Kasem, Campbell William B
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
Hypertension. 2008 Jul;52(1):150-5. doi: 10.1161/HYPERTENSIONAHA.107.104158. Epub 2008 May 19.
Angiotensin (Ang) II regulates adrenal steroidogenesis and adrenal cortical arterial tone. Vascular metabolism could decrease Ang II concentrations and produce metabolites with vascular activity. Our goals were to study adrenal artery Ang II metabolism and to characterize metabolite vascular activity. Bovine adrenal cortical arteries were incubated with Ang II (100 nmol/L) for 10 and 30 minutes. Metabolites were analyzed by mass spectrometry. Ang (1-7), Ang III, and Ang IV concentrations were 146+/-21, 173+/-42 and 58+/-11 pg/mg at 10 minutes and 845+/-163, 70+/-14, and 31+/-3 pg/mg at 30 minutes, respectively. Concentration-related relaxations of U46619-preconstricted cortical arteries to Ang II (maximum relaxation=29+/-3%; EC(50)=3.4 pmol/L) were eliminated by endothelium removal and inhibited by the NO synthase inhibitor, nitro-L-arginine (30 micromol/L; maximum relaxation=14+/-7%). Ang II relaxations were enhanced by the angiotensin type-1 receptor antagonist losartan (1 micromol/L; maximum relaxation=41+/-3%; EC(50)=11 pmol/L). Losartan-enhanced Ang II relaxations were inhibited by nitro-L-arginine (maximum relaxation=18+/-5%) and the angiotensin type-2 receptor antagonist PD123319 (10 micromol/L; maximum relaxation=27+/-5%). Ang (1-7) and Ang III caused concentration-related relaxations with less potency (EC(50)=43 and 24 nmol/L, respectively) but similar efficacy (maximum relaxations=39+/-3% and 48+/-5%, respectively) as losartan-enhanced Ang II relaxations. Ang (1-7) relaxations were inhibited by nitro-L-arginine (maximum relaxation=16+/-4%) and the Ang (1-7) receptor antagonist 7(D)-Ala-Ang (1-7) (1 micromol/L; maximum relaxation=10+/-3%) and eliminated by endothelium removal. Thus, Ang II metabolism by adrenal cortical arteries to metabolites with decreased vascular activity represents an inactivation pathway possibly decreasing Ang II presentation to adrenal steroidogenic cells and limits Ang II vascular effects.
血管紧张素（Ang）II调节肾上腺类固醇生成和肾上腺皮质动脉张力。血管代谢可降低Ang II浓度并产生具有血管活性的代谢产物。我们的目标是研究肾上腺动脉Ang II代谢并表征代谢产物的血管活性。将牛肾上腺皮质动脉与Ang II（100 nmol/L）孵育10分钟和30分钟。通过质谱分析代谢产物。Ang（1-7）、Ang III和Ang IV的浓度在10分钟时分别为146±21、173±42和58±11 pg/mg，在30分钟时分别为845±163、70±14和31±3 pg/mg。U46619预收缩的皮质动脉对Ang II的浓度依赖性舒张作用（最大舒张率=29±3%；半数有效浓度（EC50）=3.4 pmol/L）在去除内皮后消失，并被一氧化氮合酶抑制剂硝基-L-精氨酸（30 μmol/L；最大舒张率=14±7%）抑制。血管紧张素1型受体拮抗剂氯沙坦（1 μmol/L；最大舒张率=41±3%；EC50=11 pmol/L）增强了Ang II的舒张作用。氯沙坦增强的Ang II舒张作用被硝基-L-精氨酸（最大舒张率=18±5%）和血管紧张素2型受体拮抗剂PD123319（10 μmol/L；最大舒张率=27±5%）抑制。Ang（1-7）和Ang III引起浓度依赖性舒张，效力较低（EC50分别为43和24 nmol/L），但与氯沙坦增强的Ang II舒张作用效果相似（最大舒张率分别为39±3%和48±5%）。Ang（1-7）的舒张作用被硝基-L-精氨酸（最大舒张率=16±4%）和Ang（1-7）受体拮抗剂7（D）-丙氨酸-Ang（1-7）（1 μmol/L；最大舒张率=10±3%）抑制，并在去除内皮后消失。因此，肾上腺皮质动脉将Ang II代谢为血管活性降低的代谢产物代表了一种失活途径，可能会减少Ang II向肾上腺类固醇生成细胞的呈现，并限制Ang II的血管效应。
