Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity
Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity
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DOI：
10.1152/ajpregu.1998.274.1.r255
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发表时间：
1998-01-01
影响因子：
2.8
通讯作者：
Sonnenberg, H
中科院分区：
文献类型：
--
作者：
Melo, LG;Veress, AT;Sonnenberg, H
心房利钠肽（ANP）是一种由心脏产生的肽类激素，具有慢性扩张作用。具有pro-ANP基因纯合破坏（-/-）的敲除小鼠不能产生ANP，并且相对于它们的野生型（+/+）同胞是高血压的。先前的研究表明，动脉血压（ABP）进一步增加清醒的-/-小鼠保持2周的2%的盐，但没有在麻醉的-/-小鼠1周后，8%的盐。为了确定观察到的盐对-/-小鼠ABP影响的不一致性是否是由于盐摄入量增加的持续时间和/或动物的意识状态，我们在用氯胺酮-甲苯噻嗪麻醉的成年+/+和-/-小鼠中从体外颈动脉导管测量ABP，（LS; 0.008%NaCl）-或高盐（HS; 8%NaCl）-饮食3-4周。+/+小鼠的清醒ABP +/- SE（mmHg）在两种饲料中均无显著差异（HS，113 +/- 3; LS，110 +/- 5）。然而，HS饮食-/-小鼠的ABP（135 +/- 3; P < 0.001）显著高于LS饮食-/-（115 +/- 2）和+/+（110 +/- 5）小鼠。麻醉降低了所有组的ABP，但基因型和饮食相关的差异被保留。在+/+小鼠中，在实验结束时收集的血液中的血浆肾素活性（PRA，ng ANG I ml-1 h-1）在2种饮食中适当地不同（HS，4.9 +/- 1.9; LS，21 +/- 2.8）。然而，在HS饮食的-/-小鼠中，PRA未能降低（HS，18 +/- 2.9; LS，19 +/- 3.7）。内皮素-l浓度与基因型无关（ET-1，pg/mg蛋白）和内皮组成型NOS（ecNOS，密度/100 μ g蛋白质）在喂食HS饮食的小鼠的肾脏中显著升高（ET-1 -/-，31 +/- 4.7和+/+，32 +/- 4.1; ecNOS -/-，160 +/- 19和+/+，156 +/- 19）（ET-1 -/-，19 +/- 1.9和+/+，21 +/- 1.8; ecNOS -/-，109 +/- 13和+/+，112 +/- 18）。我们的结论是，无论警觉状态，-/-小鼠盐敏感性高血压后，长期喂养HS，部分原因是由于他们无法降低PRA，而特定的肾脏上调ecNOS和ET-1响应HS摄入量可能是一个ANP独立的适应性调整，旨在改善肾功能和抵消盐的升压作用。
Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP +/- SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 +/- 3; LS, 110 +/- 5). However, on HS diet -/- mice had significantly higher ABP (135 +/- 3; P < 0.001) than both -/- (115 +/- 2) and +/+ (110 +/- 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the genotype-and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I ml-l h-l) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 +/- 1.9; LS, 21 +/- 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 +/- 2.9; LS, 19 +/- 3.7). Independent of genotype, concentration of endothelin-l (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 mu g protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 +/- 4.7 and +/+, 32 +/- 4.1; ecNOS -/-, 160 +/- 19 and +/+, 156 +/- 19) compared with mice fed on LS diet (ET-1 -/-, 19 +/- 1.9 and +/+, 21 +/- 1.8; ecNOS -/-, 109 +/- 13 and +/+, 112 +/- 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting teh pressor effect of salt.