Inhibition of pressure natriuresis in mice lacking the AT(2) receptor

Background Angiotensin II type 2 (AT(2)) receptor knockout mice have higher blood pressures than wild-type mice; however, the hypertension is imperfec tly defined. We tested the hypothesis that renal mechanisms could be contri butory. Methods. We conducted pressure-natriuresis-diuresis experiments, measured r enal cortical and medullary blood flow by laser Doppler methods, and explor ed cytochrome P450-dependent arachidonic acid metabolism by means of revers e transcription-polymerase chain reaction. Results. Blood pressure was 15 mm Hg higher in ATP receptor knockout mice t han in controls, and pressure diuresis and natriuresis curves were shifted rightward. At similar renal perfusion pressures (113 to 118 mm Hg), wild-ty pe mice excreted threefold more sodium and water than AT(2) receptor knocko ut mice. Fractional sodium and water excretion curves were shifted rightwar d in parallel. Renal blood flow ranged between 6.72 and 7.88 mL/min/g kidne y wet weight (kwt) in wild-type and between 5.84 and 6.15 mL/min/g kwt in A TI receptor knockout mice. Renal vascular resistance was increased in AT(2) A receptor knockout mice. Cortical blood flow readings leveled at 2.5 V in wild-type and 1.5 V in AT(2) receptor knockout mice. Medullary blood flow r eadings ranged between 0.8 and 1.0 V and increased 116% in wild-type mice a s renal perfusion pressure was increased. This increase did not occur in AT (1) receptor knockout mice. The glomerular filtration rate (GFR) was simila r in both groups at approximately 1 mL/min/g kwt. Renal microsomes from AT( 2) receptor knockout mice had less activity in hydroxylating arachidonic ac id to 20-hydroxyeicosatetraenoic acid (20-meter) than controls, whereas ren al AT(1) receptor gene expression was increased in AT(2) receptor knockout mice. Conclusions. Hemodynamic and tubular factors modify renal sodium handling i n AT(2) receptor knockout mice and may cause hypertension. AT(2) receptor d isruption induces alterations of other regulatory systems, including altere d arachidonic acid metabolism, that may contribute to the intrarenal differ ences observed between AT(2) receptor knockout and wild-type mice.