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J Am Soc Nephrol 13:2860-2868, 2002
© 2002 American Society of Nephrology

A Mouse Model of Angiotensin II Slow Pressor Response: Role of Oxidative Stress

Noritaka Kawada*,{dagger}, Enyu Imai{dagger}, Alexsander Karber*, William J. Welch* and Christopher S. Wilcox*

*Center for Hypertension and Renal Disease Research, Georgetown University, Washington, DC; and {dagger}Division of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

Correspondence to Dr. Christopher S. Wilcox, Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Road, NE, PHCF6003, Washington, DC 20007-2197. Phone: 202-678-9183; Fax: 202-687-7893;E-mail: wilcoxch{at}geogetown.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. The slow pressor response to prolonged infusions of angiotensin II (AngII) entails a delayed rise in BP. This study investigated the hypothesis that the response depends on the generation of oxidative stress. The BP and renal functional response of mice to graded doses (200, 400, and 1000 ng · kg-1 · min-1) of subcutaneously infused AngII was studied. The SBP of conscious mice increased by day 3 at AngII1000 but showed a delayed rise by days 9 to 13 (slow pressor response) at the lower rates of AngII infusion. By day 13, there was a graded increase in SBP with the rate of AngII infusion (Vehicle, -2.6 ± 2.6%; AngII200, +14.1 ± 5.0%; AngII400, +31.9 ± 1.9%; AngII1000, +43.2 ± 5.5%). The MAP measured under anesthesia rose significantly (P < 0.001) with AngII400 at 14 d (Vehicle, 85 ± 2 mmHg; AngII400, 100 ± 3 mmHg). When studied at day 6, the MAP of AngII400 rats was not elevated (88 ± 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 ± 0.05 versus 1.25 ± 0.05 ml · min-1 · g-1; P < 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 ± 1.2 versus 37.2 ± 0.8%; P < 0.001). From day 6 through day 14, the MAP had increased (P < 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 ± 0.04 ml · min-1 · g-1 (P < 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 ± 0.6 versus 19.2 ± 1.2 mmHg · ml-1 · min-1 · g-1; P < 0.05). Renal excretion of 8-iso PGF2{alpha} was increased in AngII400 group at day 12 (2.52 ± 0.35 versus 5.85 ± 0.78 pg · day-1; P < 0.01). The permeant superoxide dismutase mimetic tempol reduced the effects of AngII400 on the SBP (-1.7 ± 5.8%; P < 0.01), the MAP (87 ± 4 mmHg; P < 0.01), and the RVR (15.2 ± 0.5 mmHg · ml-1 · min-1 · g-1; P < 0.05) at day 14 and the renal 8-iso PGF2{alpha} excretion (3.53 ± 0.71 pg · d-1; P < 0.05) at day 12. It is concluded that the AngII infused mouse is a valid model for the slow pressor response. There is an early rise in GFR and FF, consistent with increased postglomerular vascular resistance and a late rise in RVR with a fall in GFR, consistent with increased preglomerular vascular resistance that is accompanied by a rise in BP. There is evidence of increased oxidative stress that is implicated in the increase in the BP and RVR in this model.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The angiotensin II (AngII) slow pressor response is a gradually developing increase in BP (BP) with an initially subpressor rate of infusion (1–4). The slow pressor response was first described in rats in 1963, (1) and subsequently has been demonstrated in rabbits, dogs and man (5). Whereas the plasma AngII levels increase by about 80-fold during an immediate pressor response, they are elevated within a physiologic level of 2- to sixfold during a slow pressor response (6). A slow pressor response is seen also with the thromboxane A2/prostaglandin H2 (TP) receptor mimetic, U-46619 (7,8). This slow pressor response has been considered an excellent model for renal hypertension in which both AngII type I (AT1) and TP receptor have been implicated (9). However, a united concept of physiologic basis for this response has remained elusive. Recent studies have shown that the AngII slow pressor response elicits oxidative stress (10–21), but its causal role in the rise in BP and renal vascular resistance is not established. Interestingly, U-46619 also elicits oxidative stress, which has been implicated in renal afferent arteriolar vasoconstriction (22). Oxidative stress can induce hypertension by many mechanisms, including a reduction in the bioactivity of nitric oxide (NO). (23) The first aim was to establish a mouse model of AngII slow pressor response. In addition to the physiologic relevance of this model, mice should be useful to investigate the role of genes that may account for the slow pressor response (24–27). The second aim of this study was to evaluate the role of oxidative stress in the slow pressor response to AngII. Whole animal oxidative stress and lipid peroxidation were assessed from the excretion of 8-isoprostane prostaglandin F2{alpha} (8-ISO) that is generated by the interaction of oxygen free radicals (O2·-) with arachidonate (28,29). The functional role of oxidative stress was assessed from the response to prolonged infusion of tempol, which is a membrane permeant nitroxide radical that acts as a superoxide dismutase (SOD) mimetic (30,31).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Pathogen-free male C57/black6 mice (weight 18 to 22g) (Taconic Lab., Germantown, NY, USA) were housed in a quiet room at 25°C with a 12-h light/dark cycle and free access to food and water. This study was approved by the Georgetown University Animal Care and Use Committee.

Prolonged Infusion of AngII and Tempol
Mice were anesthetized with pentobarbital sodium (50 mg · kg-1 IP) to allow the subcutaneous (SC) implantation of osmotic minipumps (model 1002; Alza Co, Palo Alto, CA, USA). AngII (Peninsula Laboratory, San Carlos, CA, USA) was dissolved in 0.154M NaCl for infusion at 0 (vehicle, V), 200, 400 and 1000 ng · kg-1 · min-1 (AngII200, AngII400, and AngII1000). To investigate the effects of tempol on AngII slow pressor response, tempol (Sigma, St. Louis, MO, USA) was dissolved in 0.154M NaCl and added to separate minipumps to deliver it at 200 nmol · kg-1 · min-1 with (AngII400/tempol) or without AngII. This dosage of tempol was based on our studies in rats (32).

Systolic BP (SBP) Measurement
SBP was measured between 8 and 11 a.m. in awake mice by the tail-cuff plethysmography method (Visitech Systems Inc., Apex, NC, USA). Measurements were made on at least 2 occasions before the implantation of minipumps. After implantation of minipumps, the SBP of mice was measured at day 3, 6, 10 and 13. SBP values were derived from an average of 6 to 8 measurements per animal at each time point. {Delta}SBP were calculated by the %changes in the SBP from day 0.

Renal Function Studies
Six or 14 d after implantation of the minipumps, mice were prepared for clearance experiments. Mice were anesthetized with a combination of inactin (50 mg · kg-1 IP) and ketamine (10 mg · kg-1 IP). Supplemental doses of anesthesia (ketamine 5 mg · kg-1) were administered intramuscularly as required. The mice were placed on a servo-controlled surgical table that maintained their body temperature at 37°C. A tracheostomy was performed with PE-90 tubing. The right jugular vein was catheterized with PE tubing for fluid infusion. The right femoral artery was cannulated with PE tubing for continuous measurement of mean arterial BP (MAP) and blood sampling. These catheters were pulled out under heat to a size appropriate for cannulation (200–300µm). The MAP was monitored with a Powerlab system (ADInstuments, Castle Hill, NSW, Australia). The bladder was catheterized via a suprapubic incision with PE-50 tubing for urine collections. During surgery, 0.154M NaCl containing 2% bovine serum albumin (Sigma, St. Louis, MO, USA) was infused iv at 0.6ml · hr-1. After surgery, the iv infusion was changed to 0.154M NaCl containing 1.5% albumin, [3H]-para-aminohippurate (PAH) (New England Nuclear Inc., Boston, MA, USA) and [14C]-inulin (NEN, Boston, MA, USA) and infused at a rate of 0.35ml · hr-1. After a 60-min equilibration period, 2 consecutive 30-min urine collections and an arterial blood sample were obtained to determine whole kidney function, hematocrit (Hct) and plasma electrolytes. PAH and inulin clearances were determined in groups of mice at: AngII400 at day6 (n = 6), AngII400 at day14 (n = 8), tempol alone at day14 (n = 8), AngII400/tempol at day14 (n = 6) and Vehicle at day14 (n = 8).

Renal Excretion of 8-iso PGF2{alpha}
At day 12 after the implantation of osmotic minipumps, tempol (n = 5), AngII400 (n = 6), AngII400/tempol (n = 6), and Vehicle (n = 6) mice were placed in metabolic cages specifically modified for mice (Nalgene Nunc International, Rochester, NY, USA). Urine was collected for 24 h into antibiotics (penicillin G: 0.8 mg, streptomycin: 2.6 mg, and amphotericin B: 5.0 mg). Total 8-iso PGF2{alpha} in urine was purified, extracted by a method we have developed and validated in the rat and assayed with an enzyme immunoassay (EIA) procedure (Cayman Chemical, Ann Arbor, MI, USA) (32).

Chemical Methods
Inulin and PAH concentrations in the urine and serum were determined by dual measurement of [14C] and [3H]. The GFR (GFR) was calculated from the clearance of inulin, renal plasma flow (RPF) from the clearance of PAH. In pilot studies, we determined that the renal excretion of PAH in mice averaged 70%. Therefore, we corrected the clearance of PAH, assuming a 70% extraction to calculate RPF. The filtration fraction (FF) was calculated as GFR/RPF. The renal blood flow (RBF) was calculated as RPF · (100-Hct)-1. The renal vascular resistance (RVR) was calculated as MAP/RBF. All values are expressed per gram of kidney weight.

Statistical Analyses
Results are expressed as mean ± SEM. Statistical analysis were performed with 1-way ANOVA or with 2-way ANOVA, followed by t test. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
SBP of Mice Infused with AngII
Figure 1A shows the %changes in SBP from day 0 measured by tail cuff technique in groups of conscious mice infused with vehicle or graded doses of AngII from day 0 through day 13. There were no significant differences in the baseline SBP between groups at day 0 (Vehicle: 107 ± 2 mmHg, AngII200: 104 ± 2 mmHg, AngII400: 99 ± 4 mmHg, and AngII1000: 101 ± 2 mmHg). The vehicle group showed no changes of the SBP through the 13 d experimental period. At day 13, all of the AngII treated groups showed significant (P < 0.05) elevation of SBP in a dose dependent manner (Vehicle: -2.6 ± 2.6%, AngII200: +14.1 ± 5.0%, AngII400: +31.9 ± 1.9%, and AngII1000: +43.2 ± 5.5%). At day 6, no significant elevation of SBP was observed in AngII200 (+2.3 ± 2.4%) or AngII400 (+7.9 ± 3.1%) groups compared to the vehicle group (+2.2 ± 2.9%). In contrast, the SBP of AngII1000 group at day 3 was higher than the vehicle group (+21.9 ± 3.3%, P < 0.05). This demonstrates that infusion of AngII at 200 and 400 ng · kg-1 · min-1 is a valid model of the slow pressor response in mice. Therefore, a dose of AngII of 400 ng · kg-1 · min-1 was selected for further study.



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  		Figure 1. Panel A depicts the changes in SBP in conscious mice infused SC with AngII of 200, 400 and 1000 ng · kg-1 · min-1 or vehicle from day 0 through day 13. Panel B depicts MAP under anesthesia in mice infused with vehicle, an AngII at a dose of 400 ng · kg-1 · min-1 for 6 days, or for 14 days.

*, P < 0.05 versus vehicle

 
MAP of Mice Infused with AngII at a Dose 400 ng · kg-1 · min-1 for 6 and 14 d
Figure 1B shows the MAP of mice infused with AngII at a dose 400 ng · kg-1 · min-1 for 6 and 14 d. The MAP was measured by direct intra-arterial catheterization under anesthesia. At day 14, the MAP of the AngII400 group (100 ± 3 mmHg) was significantly (P < 0.001) higher than the vehicle (85 ± 2 mmHg). However, at day 6, there was no difference in the MAP (88 ± 2 mmHg) compared to the vehicle. After day 6, the MAP increased (P < 0.01 versus AngII400 at day 6).

Renal Function of Mice Infused with AngII at a dose 400 ng · kg-1 · min-1 for 6 and 14 d
Figure 2A shows the GFR in mice infused with AngII at a dose 400 ng · kg-1 · min-1 for 6 and 14 d. The GFR of the AngII400 group at day 6 (1.25 ± 0.05 ml · min-1 · g-1) was higher (P < 0.05) than the vehicle (1.05 ± 0.05 ml · min-1 · g-1), but, by day 14, the GFR had fallen (1.05 ± 0.04 ml · min-1 · g-1, P < 0.01 versus AngII400 at day 6) and was no longer different from the vehicle group. The RBF (Figure 2B) of the AngII400 group at day 14 (5.29 ± 0.22 ml · min-1 · g-1) was lower (P < 0.001) than the vehicle (6.32 ± 0.35 ml · min-1 · g-1). In contrast to the GFR, no rise in RBF was observed at day 6 (5.74 ± 0.24 ml · min-1 · g-1). The FF (Figure 2C) of the AngII400 group at day 6 (37.2 ± 0.8%) and at day 14 (34.4 ± 1.7%) was higher (P < 0.001) than the vehicle (28.8 ± 1.2%). Although the BP became elevated after day 6, there was no further change of FF between day 6 and day 14. At day 14, the RVR (Figure 2D) of the AngII400 group (19.2 ± 1.2 mmHg · ml-1 · min-1 · g-1) was significantly (P < 0.05) higher than the vehicle (13.8 ± 0.9 mmHg · ml-1 · min-1 · g-1). However, at day 6, there was no difference in the RVR (15.3 ± 0.6 mmHg · ml-1 · min-1 · g-1) compared to the vehicle. After day 6, the RVR increased significantly (P < 0.05 versus AngII400 at day 6).



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  		Figure 2. GFR (Panel A), RBF (Panel B), FF (Panel C) and RVR (Panel D) of mice infused with vehicle, or AngII at a dose of 400 ng · kg-1 · min-1 for 6 days, or for 14 days.

 
Hematocrit, Total Body and Kidney Weights, Heart Rate, Plasma Electrolytes, and Urine Volume
Table 1 shows data for mice infused with AngII ± tempol. There were no differences in total body and kidney weights, %change in body weight, Hct, plasma electrolytes or urine volume between the vehicle and the AngII400/tempol group. In the AngII400 group at day 14, the %change of body weight was lower (P < 0.05) and urine volume was higher (P < 0.05) compared to the vehicle or the AngII400/tempol group at day 14. The impaired gain of total BW and higher output of urine are compatible with previous report of the slow pressor model in rats (33). The HR of the tempol group was lower (P < 0.05) than the vehicle. In the AngII1000 group at day 14, the Hct and the output of urine are higher (P < 0.05) and the plasma potassium level is lower (P < 0.05) compared to the vehicle or the AngII400 groups.


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  		Table 1. Total body and kidney weight, heart rate, hematocrit, plasma electrolytes, and urine volume of mice infused with AngII and tempola
 
SBP and MAP of Mice Infused with AngII ± Tempol
Figure 3A shows the %changes in SBP from day 0 ({Delta}SBP) measured by tail cuff technique in groups of conscious mice infused with vehicle, tempol or AngII ± tempol at day 0, 6 and day 13. There were no significant differences in the baseline SBP in each group at day 0 (Vehicle: 107 ± 2 mmHg, tempol: 105 ± 2 mmHg, AngII400: 99 ± 4 mmHg, and AngII400/tempol: 106 ± 3 mmHg). At day 6, AngII or tempol showed no significant effect on SBP (Vehicle: +2.2 ± 2.9%, tempol: +2.0 ± 3.3%, AngII400: +7.9 ± 3.1%, and AngII400/tempol: +7.2 ± 4.0%). At day 13, the {Delta}SBP in vehicle, tempol, AngII400 and AngII400/tempol infusion groups were -2.6 ± 5.0, +1.8 ± 1.5, +31.9 ± 1.9 and -1.7 ± 5.8%, respectively. Infusion of tempol alone for 13 d had no effect on SBP. AngII400 infusion for 13 d significantly (P < 0.01) increased the SBP and tempol significantly (P < 0.01) reduced the effect of AngII on SBP. Figure 3B shows the MAP of groups of mice infused with AngII or tempol alone or in combination. The MAP was measured by direct intra-arterial catheterization under anesthesia. At day 14, the MAP of the vehicle, tempol, AngII400 and AngII400/tempol infusion groups were 85 ± 2, 86 ± 2, 100 ± 3 and 87 ± 4 mmHg, respectively. Infusion of tempol alone for 14 d had no effect on MAP. AngII400 infusion for 14 d significantly (P < 0.01) increased the MAP and tempol significantly (P < 0.01) reduced the effect of AngII on MAP.



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  		Figure 3. Panel A depicts the %changes in SBP in conscious mice infused SC with vehicle, tempol (200 mmol · kg-1 · min-1), AngII (400 ng · kg-1 · min-1), or a combination of AngII (400 ng · kg-1 · min-1) with tempol (200 mmol · kg-1 · min-1) at day 0, 6 and day 13. Panel B depicts MAP under anesthesia in mice infused with vehicle or tempol (200 mmol · kg-1 · min-1) for 14 days or AngII (400 ng · kg-1 · min-1) for for 14 days, or a combination of AngII (400 ng · kg-1 · min-1) with tempol (200 mmol · kg-1 · min-1) for 14 days.

 
Renal Function of Mice Infused with AngII ± Tempol
Figure 4A shows the GFR in mice after 14 d of vehicle or tempol, or AngII ± tempol infusion. The GFR in the vehicle, tempol, AngII400 and AngII400/tempol infusion groups were 1.05 ± 0.05, 1.17 ± 0.06, 1.05 ± 0.04 and 1.29 ± 0.06 ml · min-1 · g-1, respectively. Infusion of tempol alone for 14 d significantly (P < 0.001) increased the GFR. AngII400 infusion for 14 d had no effect on GFR and tempol had no effect on the AngII action on the GFR. Figure 4B shows the RBF in mice after 14 d of vehicle or tempol, or AngII ± tempol infusion. The RBF in vehicle, tempol, AngII400 and AngII400/tempol infusion groups were 6.32 ± 0.35, 6.62 ± 0.29, 5.29 ± 0.22 and 5.73 ± 0.25 ml · min-1 · g-1, respectively. Infusion of tempol alone for 14 d had no effect on the RBF. AngII400 infusion for 14 d significantly (P < 0.001) reduced the RBF and tempol had no effect on the AngII action on the RBF. Figure 4C shows the FF in mice after 14 d of vehicle or tempol, or AngII ± tempol infusion. The FF in vehicle, tempol, AngII400 and AngII400/tempol infusion groups were 28.8 ± 1.2, 29.2 ± 0.8, 34.4 ± 1.7 and 38.9 ± 2.1%, respectively. Infusion of tempol alone for 14 d had no effect on the FF. AngII400 infusion for 14 d significantly (P < 0.001) increased the FF and tempol had no effect on the AngII action on the FF. Figure 4D shows the RVR in mice after 14 d of vehicle or tempol, or AngII ± tempol infusion. The RVR in vehicle, tempol, AngII400 and AngII400/tempol infusion groups were 13.8 ± 0.9, 13.1 ± 0.6, 19.2 ± 1.2 and 15.2 ± 0.5 mmHg · ml-1 · min-1 · g-1, respectively. Infusion of tempol alone for 14 d had no effect on the RVR. AngII400 infusion for 14 d significantly (P < 0.001) increased the RVR and tempol significantly reduced (P < 0.05) the effect of AngII on RVR.



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  		Figure 4. GFR (Panel A), RBF (Panel B), FF (Panel C) and RVR (Panel D) of mice. See legend to Figure 3.

 
Renal Excretion of 8-iso PGF2{alpha}
Figure 5 shows the renal excretion of 8-iso PGF2{alpha} in mice after 12 d of vehicle or tempol, or AngII ± tempol infusion. The renal excretion of 8-iso PGF2{alpha} in the vehicle, tempol, AngII400 and AngII400/tempol infusion groups are 2.52 ± 0.35, 2.57 ± 0.43, 5.85 ± 0.78 and 3.53 ± 0.71 pg · day-1, respectively. Infusion of tempol alone for 12 d had no effect on the renal excretion of 8-iso PGF2{alpha}. AngII400 infusion for 12 d significantly (P < 0.01) increased the excretion of 8-iso PGF2{alpha} and tempol significantly reduced the effect of AngII on the excretion of 8-iso PGF2{alpha}.



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  		Figure 5. Renal excretion of 8-iso PGF2{alpha} in mice. See legend to Figure 3.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We investigated the dose response relationship for AngII infusion given over 6 to 14 d in mice. The results show that a subcutaneous infusion of AngII at 400 ng · kg-1 · min-1 does not elevate the SBP of conscious mice, or the MAP of anesthetized mice by day 6, yet leads to clear-cut BP elevation by days 10 to 13. Therefore, this appears to be a valid model of the slow pressor response in mice. Higher rates of infusion of AngII at 1000 ng · kg-1 · min-1 caused an abrupt increase in SBP. Furthermore, AngII at 1000 ng · kg-1 · min-1 over 14 d led to an increase in Hct and hypokalemia. AngII-stimulated aldosterone production could be an explanation for this hypokalemia, which has been associated with interstitial damage and tubular dysfunction (34–37). These secondary effects of AngII may have influenced the BP and the renal function of AngII1000 group. Thus, AngII at a dose of 400 ng · kg-1 · min-1 is a more useful and straightforward model for the investigation of AngII action.

This is the first study in mice of the time-dependent changes in renal function with graded doses of AngII. These results show a biphasic action of subpressor doses of AngII on renal function. By day 6, there was an increase of the GFR and FF without a change in the RBF. This renal hemodynamic change preceded any elevation of BP in the AngII400 group. Analysis of single nephron segmental vascular resistance will be required to quantify the site of the change in RVR in the mouse model. However, these results are consistent with a preferential action of AngII on the kidney at this earlier time point, perhaps on the post-glomerular vessels. During continuous AngII infusion at 400 ng · kg-1 · min-1 from day 6 through day 14, the GFR was reduced and the RVR was increased, accompanied by an elevation of BP. This is consistent with the conclusion of Stevenson et al. (38) that AngII elevates the pre-glomerular vascular resistance in the rat. This could play a key role in the maintenance of hypertension in the established phase of the AngII slow pressor response.

Having established the conditions for a slow pressor response in the mouse, we investigated the relationships between this response and the generation of oxidative stress. 8-iso PGF2{alpha} can be generated by a non-enzymatic oxidative reaction of arachidonic acid (28,29). Measurements of 8-iso PGF2{alpha} have been used to quantitate oxidative stress in vitro and in vivo (15,17,39). We demonstrated that the renal excretion of 8-iso PGF2{alpha} was increased in the mice infused with AngII400. This extends to the mouse the original observation of Romero et al. in rat and swine that prolonged slow pressor infusion of AngII increased the plasma level of 8-iso PGF2{alpha} (3). Tempol is a membrane permeant nitroxide that acts as an SOD mimetic. It catalyzes the conversion of O2· - radicals to hydroperoxides (30,31). Tempol has been used to investigate the role of O2· - radicals in several pathophysiologic conditions, such as ischemia-reperfusion (40,41), radiation (42,43), diabetes mellitus (44), and hypertension (32,45,46). Tempol significantly reduced the effect of sub-pressor dose of AngII on the renal excretion of 8-iso PGF2{alpha}. This confirms that tempol infusion is a valid method to prevent the oxidative stress associated with the AngII infusion. Tempol infused alone for 14 d significantly reduced the HR and increased the GFR. Interestingly, tempol significantly reduced the effect of sub-pressor dose of AngII on the BP and the RVR (Fig 3, 4D), which were observed from day 6 through day 14 (Fig 1, 2D). In the present study, tempol did not affect the AngII action on GFR at day 14. However, as shown in Fig 2A, AngII increases the GFR at day 6 and decreases the GFR to the level of the vehicle group at day 14. Interestingly, although tempol significantly reduced the AngII action on BP, the RBF was maintained. These results indicate that oxidative stress generated by AngII is important for the associated development of hypertension and renal vasoconstriction.

The mechanisms of the renal vascular responses to tempol are not established. One possibility is that the primary effect of tempol is to prevent a rise in MAP, and thereby to prevent an autoregulatory adjustment of pre-glomerular vascular resistance. However another explanation is suggested from the results of studies in the spontaneously hypertensive rat (SHR). This rat develops oxidative stress before the development of hypertension (47). In this model, pre-glomerular vascular resistance is also increased before the appearance of hypertension. This renal vascular effect has been associated with enhanced action of AngII on type I (AT1) receptors (48–50), and is related to a diminished action of NO in the juxtaglomerular apparatus (JGA). Local microperfusion of tempol into the renal interstitium via the efferent arteriole enhances the transmission of NO signals from the lumen of the macula densa, and blunts the TGF-induced vasoconstriction of the afferent arteriole (49). This defective NO transmission is attributed to AngII since administration of an angiotensin receptor blocker (ARB), but not equi-effective non-specific antihypertensive therapy, corrects the response. These results favor an effect of AngII on the afferent arteriole early in the development of hypertension, which is promoted by the development of oxidative stress and leads to decreased buffering by NO. However, the results of the present study do not allow us to destinguish between a primary effect of tempol to lower BP (and an autoregulatory reduction in RVR) or a primary effect of tempol to reduce RVR.

In conclusion, we have characterized a new mouse model of the AngII slow pressor response. There is an early change in renal function that precedes a change in BP, whether measured non-invasively in conscious mice by SBP, or directly by intra-arterial recording in anesthetized mice. Therefore, the rise in BP may be a response to a primary change in the kidney. The early, pre-hypertensive change in renal function is consistent with a rise in post-glomerular vascular resistance that is followed by a rise in pre-glomerular vascular resistance that accompanies the rise in BP. The response is accompanied by oxidative stress that is implicated in the increase in the BP or renal vascular resistance and the fall in GFR in this model. There is a limitation in our renal hemodynamic study. This study was performed under anesthesia, which may counteract some of AngII’s actions. The actual changes of renal hemodynamics in this model are expected to be stronger than our present results obtained under anesthesia. Further investigations of the BP and renal hemodynamics in conscious mice without stress, probably based on the developing telemetry technique are needed to assess the full effect of AngII independent of anesthesia. Further micropuncture studies of single nephron GFR and segmental vascular resistance in the kidney will be necessary to confirm the site of action of AngII and oxidative stress in this model. This simple model of hypertension could be applied in mice with single gene mutations to investigate the role of specific gene products in the progressive increase in renal vascular resistance and BP and the oxidative stress that accompanies the slow pressor response.


   Acknowledgments
 
This work was supported by grants from the NIDDK (DK-49870 and DK-36079), the NHLBI (HL-68686) of the NIH and the grant support for the overseas research by the Osaka Heart Club (Boston Scientific Japan) and the Mochida Pharmacia foundation, and by funds from the George E. Schreiner Chair of Nephrology.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Dickinson CJ, Lawrence JR: A slowly developing pressor response to small concentration of angiotensin. Lancet 1: 1354–1356 1963[Medline]
  2. Brown A, Casals-Stenzel J, Gofford S, Lever AF, Morton JJ: Comparison of fast and slow pressor effects of angiotensin II in the conscious rat. Am J Physiol 241: H381–H388, 1981
  3. Romero JC, Reckelhoff JF: Role of angiotensin and oxidative stress in essential hypertension. Hypertension 34: 943–949, 1999[Abstract/Free Full Text]
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Received for publication December 27, 2001. Accepted for publication August 6, 2002.




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