Melo L G, Veress A T, Chong C K, Pang S C, Flynn T G, Sonnenberg H
Department of Physiology, University of Toronto, Ontario, Canada.
Am J Physiol. 1998 Jan;274(1):R255-61. doi: 10.1152/ajpregu.1998.274.1.R255.
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 the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I.ml-1.h-1) 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-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 micrograms 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 the pressor effect of salt.
心房利钠肽（ANP）是一种由心脏产生的肽类激素，具有慢性降压作用。纯合缺失前ANP基因（-/-）的基因敲除小鼠无法产生ANP，相对于其野生型（+/+）同胞而言具有高血压症状。先前的研究表明，在2%盐浓度的环境中饲养2周的清醒-/-小鼠动脉血压（ABP）进一步升高，但在8%盐浓度环境中饲养1周后的麻醉-/-小鼠中并未出现这种情况。为了确定观察到的盐对-/-小鼠ABP影响的不一致是否是由于盐摄入量增加的持续时间和/或动物的意识状态所致，我们在成年+/+和-/-小鼠从氯胺酮-赛拉嗪麻醉中恢复期间及之后，通过外置颈总动脉导管测量了ABP，这些小鼠分别在低（LS；0.008% NaCl）或高（HS；8% NaCl）盐饮食中饲养3 - 4周。两种饮食条件下，+/+小鼠的清醒ABP±SE（mmHg）均无显著差异（HS组，113±3；LS组，110±5）。然而，在HS饮食条件下，-/-小鼠的ABP（135±3；P < 0.001）显著高于LS饮食条件下的-/-小鼠（115±2）和+/+小鼠（110±5）。麻醉使所有组的ABP降低，但基因型和饮食相关差异仍然存在。实验结束时采集的血液中，血浆肾素活性（PRA，ng ANG I·ml⁻¹·h⁻¹）在+/+小鼠的两种饮食条件下有适当差异（HS组，4.9±1.9；LS组，21±2.8）。然而，HS饮食条件下的-/-小鼠PRA未能降低（HS组，18±2.9；LS组，19±3.7）。与基因型无关，与喂食LS饮食的小鼠相比（ET - 1 -/-组，19±1.9和+/+组，21±1.8；ecNOS -/-组，109±13和+/+组，112±18），喂食HS饮食的小鼠肾脏中内皮素-1（ET - 1，pg/mg蛋白）浓度和内皮型组成型一氧化氮合酶（ecNOS，密度/100μg蛋白）显著升高（ET - 1 -/-组，31±4.7和+/+组，32±4.1；ecNOS -/-组，160±19和+/+组，156±19）。我们得出结论，无论警觉状态如何，-/-小鼠在长期喂食HS后都会出现盐敏感性高血压，部分原因是它们无法降低PRA，而肾脏中ecNOS和ET - 1因HS摄入而发生的特异性上调可能是一种不依赖ANP的适应性调节，旨在改善肾功能并抵消盐的升压作用。
