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Regulation of AT1‐Receptors by ARAP1 is involved in vasodilatation during sepsis‐induced hypotension
Author(s) -
Mederle Katharina,
Doblinger Elisabeth,
Kattler Veronika,
Höcherl Klaus,
Schweda Frank,
Castrop Hayo
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.909.9
Subject(s) - sepsis , angiotensin ii receptor type 1 , medicine , angiotensin ii , endocrinology , receptor , downregulation and upregulation , vasodilation , blood pressure , renin–angiotensin system , vascular resistance , septic shock , angiotensin receptor , mean arterial pressure , heart rate , chemistry , biochemistry , gene
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.