Questions:

Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors like Angiotensin II. Altered expression of Angiotensin II-type1- (AT1)-receptors might contribute to reduced vascular tone during sepsis-induced hypotension. The Angiotensin II-type1-receptor associated protein 1 (ARAP1) is expressed in smooth muscle cells of blood vessels. ARAP1 increases the surface expression of the AT1-receptor in vitro. In this study we determined baseline parameters of blood pressure homeostasis in ARAP1-deficient mice and addressed the role of ARAP1 in sepsis-induced hypotension.

Methods:

Plasma renin concentration was measured by radioimmunoassay. Glomerular filtration rate was determined in conscious mice by FITC-labeled sinistrin clearence. Mean arterial blood pressure (MAP) and heart rate under baseline conditions and following LPS injection were measured by radio-telemetry. The effect of Angiotensin II on renal vascular resistance was determined by measurement of the perfusate flow in the isolated perfused mouse kidney.

Results:

ARAP1-/- and wild type mice did not differ in glomerular filtration rate (296.4±19.9 vs. 315.2±29.5 µl/min; n=10; p=0.61) and MAP (101.6±1.6 vs.102.8±2.0 mmHg; n=6; p=0.66). Plasma renin concentration was significantly increased in ARAP1-/- mice compared to WT mice (66.2±6.1 vs. 40.8±3.7 ng AngI/ml/h; n=23; p=0.001) and was accompanied by an elevated urine osmolality (2312±0.12 vs. 1782±0.11 mosmol/kg; n=20; p=0.003). Dose-dependent changes in vascular resistance were right-shifted in isolated perfused kidneys from Arap1-/- mice. Following LPS-treatment (3mg/kg), ARAP1 mRNA expression in kidneys of WT mice was significantly downregulated to 33±10% of controls (p=0.01). MAP (84.34±1.86 mmHg vs. 90.38±1.40 mmHg; n=10; p=0.03) and heart rate (446.33±12.71 vs. 492.18±10.35 bpm; n=10; p=0.01) decreased after LPS-injection to significantly lower values in ARAP1-/- mice compared to WT mice.

Conclusion:

Our data suggest, that ARAP1 is involved in sensitization of vascular AT1-receptors. ARAP1-/- mice seem to normalize blood pressure by compensatory activation of the renin-angiotensin-aldosterone-system. However, sepsis-induced hypotension is enhanced in ARAP1-/- mice. Downregulation of ARAP1 expression during sepsis could contribute to hypotension by reduced vascular sensitivity to Ang II.