Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation

Abstract

Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO₂) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 ± 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 ± 2%) and medulla (by 17 ± 6%) at 10 ± 2 and 6 ± 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension.

Figure 1

Cortical and medullary oxygenation (pO₂) and mean arterial pressure (MAP) during 8 days of angiotensin II (AngII) infusion. Osmotic minipumps were implanted to start 350 ng/kg/min AngII infusion (dashed line). Telemetric recordings of cortical (closed circles, n = 6) and medullary (open circles, n = 7) pO₂ were recorded continuously. Values are expressed as a percentage of the baseline period before AngII infusion. MAP was determined by telemetry (dots, n = 5) in another subset of animals. Data is presented as mean of 6 h averages ± SEM. *p ≤ 0.05 in medulla, ^†p ≤ 0.05 in cortex, **p ≤ 0.01, all vs. baseline.

Figure 2

Chronic angiotensin II (AngII) infusion and hydralazine. (A) Cortical (n = 6, closed circles) and medullary (n = 7, open circles) oxygenation (pO₂) and mean arterial pressure (MAP) (n = 5, dots) during the early phase of AngII infusion. Osmotic minipumps were implanted to start 350 ng/kg/min AngII infusion (dashed line). Values are expressed as a percentage of the baseline period before AngII infusion. Data is presented as mean of 1 h averages ± SEM. (B) Medullary (n = 3) pO₂ during hydralazine administration (5–25 mg/kg/day) only or in combination with AngII infusion (350 ng/kg/min). Data is presented as mean of 1 h averages ± SD. Telemetric recordings were recorded continuously. (A,B) were derived from different subsets of animals.

Figure 3

Renal morphology. Representative photomicrographs of periodic acid Schiff stained renal sections of control (Con, left) and angiotensin II-infused (AngII, right) rats. Mild fibrosis was observed in the cortex of AngII treated rats.

Figure 4

Relation between mean arterial pressure (MAP) and oxygenation (pO₂) in cortex and medulla. In matched periods of 15 min. mean pO₂ and mean MAP were paired during a baseline period (day -4 to -1, open circles) and during angiotensin II (AngII) infusion (day 3 to 6, closed circles). The characteristic association between MAP and pO₂, observed during control conditions, disappeared in both cortex and medulla during AngII infusion. ANCOVA: p < 0.001 vs. baseline.

Figure 5

Cortical and medullary oxygenation (pO₂) and mean arterial pressure (MAP) during angiotensin II (AngII) infusion plus oral losartan for 48 hours. Losartan was added to the drinking water (300 mg/L, dashed line). Telemetric measurements of cortical (closed circles) and medullary (open circles) pO₂ were recorded continuously. Values are expressed as a percentage of the 12h-period before losartan. MAP was determined telemetrically (dots) in another subset of animals. Data is presented as mean of 1 h averages ± SEM. *p ≤ 0.05 in medulla, ^†p ≤ 0.05 in cortex, **p ≤ 0.01, all vs. the average of the 12 hours prior to losartan (set point).