Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice

Abstract

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.

Figure 1

Analysis of the effects of APA deficiency on basal blood pressure level. The systolic (A) and mean (B) blood pressure of APA^−/−, APA^+/−, and APA^+/+ mice at 3 mo (n = 9 to 15 per group) were determined by a computed tail-cuff system. Each datum point represents the mean of 2-d measurements taken after a 4-d training period. The average ± SEM for each group is represented by an open circle and a bar. *P < 0.05.

Figure 2

Effects of chronic angiotensin II infusion on systolic blood pressure. A: Daily changes in systolic blood pressure (SBP) in saline infusion (SAL)/APA^−/− (□), SAL/APA^+/+ (▪), angiotensin II infusion (ANG II)/APA^−/− (○) and ANG II/APA^+/+ (•) mice. The implantation of osmotic minipumps was done on day 0. B: The increase of SBP (ΔSBP) from baseline on day 0 to the levels on day 2 in APA^−/− and APA^+/+ mice. Values are mean ±SEM. *P < 0.05 compared with APA^+/+ mice; #P < 0.01 compared with SAL-infused mice.

Figure 3

Age-related changes of systolic blood pressure. The systolic blood pressure was measured in APA^−/− (○) and APA^+/+ (•) mice ranging from 8- to 60-wk. Values are mean ±SEM. *P < 0.05 compared with APA^+/+ mice.