Enalapril attenuates endothelin-1-induced hypertension via increased kinin survival.
Enalapril attenuates endothelin-1-induced hypertension via increased kinin survival.
复制标题
依那普利通过增加激肽存活来减轻内皮素 1 诱导的高血压。
DOI：
10.1152/ajpheart.00027.2003
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Pollock,DavidM
中科院分区：
文献类型：
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作者：
Elmarakby,AhmedA;Morsing,Peter;Pollock,DavidM
方法所有研究对象均为雄性SD大鼠(体重200-250g，Harlan实验室)，实验前在佐治亚医学院动物护理机构饲养1wk。大鼠被安置在12h：12h明暗周期的温控条件下。用Inactin(100 mg/kg ip；5-秒-丁基-5-乙基-2-硫代巴比妥酸；Sigma，圣路易斯，密苏里州)麻醉大鼠，并将其放在伺服控制的加温台上，以保持直肠温度37℃恒定。使用聚乙烯(PE)-205管子进行气管切开，以确保呼吸畅通。使用MacLab数据采集系统将导管(PE-50)插入右侧股动脉以测量平均动脉压。右侧颈静脉插管(PE-50)，股静脉插管(PE-50)，分别注入0.9%氯化钠(10 L/min)和0.9%含[~H]菊粉的生理盐水(4CIH1100g 1；10 L/min)。另一根导尿管(PE-90)被放置在膀胱内，以便收集尿液。在60分钟的平衡期后，开始30分钟的基线尿液采集期，包括在该时间点的中点采集血样。然后，不同的组大鼠分别静脉注射1)生理盐水(1ml/kg)，2)血管紧张素转换酶抑制剂依那普利(10 mg/kg)，3)血管紧张素II受体拮抗剂坎地沙坦(10 mg/kg)，4)血管肽酶抑制剂奥马曲拉(30 mg/kg)，5)缓激素受体拮抗剂REF-000359(1 mg/kg)，或6)REF-00059依那普利。随后立即输注ET-1(10pmolkg1min 1)。在ET-1输注期间，另外两个30分钟的尿液采集期是在中点采集血液样本以测量[~3H]菊糖。尿量采用重力法测量。记录血压变化，测定肾小球滤过率(GFR)作为[~3H]菊糖清除量。在初步实验中，所选剂量的依那普利、坎地沙坦和奥马曲拉能够完全阻断静脉注射血管紧张素转换酶I(100-500 ng/kg)的升压反应(数据未显示)。此外，在单独的大鼠身上也证实了所选剂量的激动素拮抗剂能够阻断静脉注射缓激肽(1-10nmol)后MAP的下降(数据未显示)。ET-1来源于美国多肽公司(加利福尼亚州桑尼维尔)。坎地沙坦、奥马帕替拉和REF-000359是阿斯利康制药公司(瑞典门达尔)慷慨赠送的礼物。依那普利来源于Sigma。统计分析。学生对配对数据的t检验用来确定控制期和实验期之间的显著差异(Statview；Abacus Concepts，Berkeley，CA)。采用协方差分析和S后验检验，确定ET-1引起的MAP和GFR变化在组间的统计学差异。这些值被报告为均数SE，P0.05被认为是显著的；所有组的n 5-8只大鼠。
METHODSAll studies were conducted on male Sprague-Dawley rats (200–250 g, Harlan Laboratories) maintained at the Medical College of Georgia animal care facility for 1 wk before the study. Rats were housed in temperature-controlled conditions with a 12 h: 12 h light-dark cycle. Rats were anesthetized with Inactin (100 mg/kg ip; 5-sec-butyl-5-ethyl-2-thiobarbituric acid; Sigma, St. Louis, MO) and placed on a servocontrolled heating table to maintain rectal temperature constant at 37 C. With the use of a polyethylene (PE)-205 tubing, a tracheostomy was performed to allow unobstructed breathing. A catheter (PE-50) was inserted in the right femoral artery for measuring MAP using a Maclab data acquisition system. The right jugular vein and femoral vein were cannulated (PE-50) for continuous infusion of 0.9% NaCl (10 l/min) and 0.9% NaCl containing [3H] inulin (4 Cih 1 100 g 1; 10 l/min), respectively. Another catheter (PE-90) was placed in the urinary bladder to allow urine collection. After a 60-min equilibration period, a 30-min baseline urine collection period was begun that included a blood sample taken at the midpoint of the period. Separate groups of rats were then given an intravenous bolus of either 1) saline (1 ml/kg), 2) the ACE inhibitor enalapril (10 mg/kg), 3) the ANG II receptor antagonist candesartan (10 mg/kg), 4) the vasopeptidase inhibitor omapatrilat (30 mg/kg), 5) the bradykinin receptor antagonist REF-000359 (1 mg/kg), or 6) REF-00059 enalapril. This was immediately followed by ET-1 infusion (10 pmolkg 1 min 1). Two additional 30-min urine collection periods were obtained during ET-1 infusion with a blood sample taken at the midpoint for measurement of [3H] inulin. Urine volume was measured gravimetrically. Blood pressure changes were recorded, and GFR was determined as the clearance of [3H] inulin. In preliminary experiments, the ability of the selected doses of enalapril, candesartan, and omapatrilat to completely block the pressor response to intravenous bolus injections of ANG I (100–500 ng/kg) was confirmed (data not shown). Furthermore, the ability of the selected dose of kinin antagonist to block the decrease in MAP following an intravevous bolus injections of bradykinin (1–10 nmol) was also confirmed in separate rats (data not shown). ET-1 was obtained from American Peptide (Sunnyvale, CA). Candesartan, omapartilat, and REF-000359 were generous gifts from AstraZeneca Pharmaceuticals (Mölndal, Sweden). Enalapril was obtained from Sigma. Statistical analysis. Student’s t-test for paired data was used to determine the significant differences between control versus experimental periods (Statview; Abacus Concepts, Berkeley, CA). ANOVA with a Scheffé’s post hoc test was used to determine the statistically significant differences between groups for ET-1-induced changes in MAP and GFR. Values are reported as means SE with P 0.05 being considered significant; n 5–8 rats in all groups.