Genetically altered mice lacking the AT_1A angiotensin II (Ang II) receptor were used to examine the role of AT_1A receptors in regulating renal hemodynamics, sodium excretion, glomerulotubular balance, and Ang II levels in plasma and kidney during normal and volume-expanded conditions.

AT_1A receptor-deficient mice and their wild-type controls were anesthetized with inactin and ketamine, and were prepared to allow intravenous infusions of solutions and measurements of aortic pressure and urine collections. Inulin and para-aminohippurate (PAH) solutions were infused intravenously for clearance determinations under conditions of euvolemia (2.5 μl/min infusion of isotonic saline) or volume-expansion conditions (12.5 μl/min). After three 30-minute urine collections, blood samples were collected, and kidneys were harvested. Plasma and kidney Ang II measurements were made by radioimmunoassay.

In the euvolemic state, mean arterial pressures (MAPs) were significantly lower in the AT_1A receptor-deficient mice (68 ± 4 mm Hg) compared with wild-type controls (89 ± 3 mm Hg). Despite the lower MAP, the glomerular filtration rate (GFR), renal plasma flow (RPF), absolute sodium excretion, and fractional sodium excretion were not significantly different between wild-type and AT_1A-/- mice. Volume expansion did not alter MAP in wild-type mice, but significantly increased MAP in the AT_1A-/- mice (68 ± 4 to 83 ± 5 mm Hg). Similar increases in GFR, RPF, absolute sodium excretion, and fractional sodium excretion in AT_1A+/+ and AT_1A-/- mice were observed. Glomerulotubular balance was not disrupted by the absence of AT_1A receptors. During euvolemia, plasma Ang II concentrations were significantly higher in the AT_1A-/- mice compared with wild-type mice (536 ± 172 vs. 198 ± 36 fmol/ml). Although volume expansion had no effect on plasma Ang II levels in the AT_1A+/+ group, plasma Ang II concentrations were markedly suppressed in the AT_1A-/- mice to levels that were not different from those in wild-type mice. In contrast, kidney tissue Ang II contents were reduced in the AT_1A-/- mice and were not significantly altered during volume expansion in either the AT_1A-/- or the AT_1A+/+ mice.

The absence of AT_1A receptors does not impair chronic regulation of renal blood flow, GFR, or glomerulotubular balance. The prompt restoration of MAP following volume expansion suggests that low blood pressure in the AT_1A receptor-deficient mice is primarily due to reduced effective plasma and extracellular fluid volume. Normalization of plasma Ang II levels with volume expansion demonstrates a dominant effect of extracellular fluid volume and blood pressure over AT_1A receptor-mediated short-loop feedback in the regulation of plasma Ang II levels.