A mouse model of angiotensin II slow pressor response: role of oxidative stress.

Abstract

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 PGF(2alpha) 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 PGF(2alpha) 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.