Regulation of AT1‐Receptors by ARAP1 is involved in vasodilatation during sepsis‐induced hypotension

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.