Abstract
Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors. Altered expression of angiotensin receptors might contribute to reduced vascular tone during sepsis. The AT1 receptor‐associated protein 1 (ARAP1) is expressed in vascular smooth muscle cells and increases the surface expression of the AT1‐receptor. Here we assessed the role of ARAP1 in sepsis‐induced hypotension.Mean arterial blood pressure (MAP) (102±2 vs.103±2 mmHg; n=6; p=.66) and glomerular filtration rate (296±20 vs. 315±30 μl/min; n=10; p=.61) were similar in ARAP1−/− and WT mice. Plasma renin concentration was increased in ARAP1−/− mice compared to WT mice (66±6 vs. 41±4 ng AngI/ml/h; n=23; p=.001). Dose‐dependent changes in vascular resistance were right‐shifted in isolated perfused kidneys from Arap1−/− mice. LPS‐treatment (3mg/kg) induced a marked downregulation of ARAP1 expression in different organs. Following LPS, MAP (84±2 vs. 90±1 mmHg; n=10; p=.03) and heart rate (446±13 vs. 492±10 bpm; n=10; p=.01) decreased to lower levels in ARAP1−/− mice compared to WT mice.Under baseline conditions, ARAP1−/− mice seem to normalize blood pressure by compensatory activation of the RAS. However, sepsis‐induced hypotension is enhanced in ARAP1−/− mice. Downregulation of ARAP1 expression during sepsis may contribute to hypotension by causing reduced vascular sensitivity to Ang II.
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