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Arginase contributes to arteriolar endothelial dysfunction following hemorrhage
Author(s) -
Johnson Fruzsina K,
Durante William,
Stewart Ronald M,
Johnson Robert A
Publication year - 2007
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.21.6.a1404-a
Subject(s) - arginase , endothelial dysfunction , endocrinology , medicine , nitric oxide , perfusion , ornithine , chemistry , nitric oxide synthase , arginine , biochemistry , amino acid
Vascular tissues express arginase that metabolizes L‐arginine (L‐Arg) to L‐ornithine and urea. Arginase competes for L‐Arg with nitric oxide synthase (NOS) and contributes to endothelial dysfunction in hypertension and diabetes. Blood loss promotes endothelial dysfunction which contributes to compromised tissue perfusion. This study tests the hypothesis that increased arginase activity contributes to endothelial dysfunction following hemorrhage. Male Sprague‐Dawley rats (300–350g) were subjected to a 45% blood loss over 5min. Blood pressure spontaneously returned to 90% of baseline within 1hr. Plasma arginase activity was increased 36hrs post‐hemorrhage by 22%. Isolated first‐order gracilis muscle arterioles were superfused with Krebs buffer and exposed to constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow (0–50μl/min). In post‐hemorrhage arterioles, flow‐induced dilation was abolished (Δ max shock: 0±0 vs unbled: 18±1μm). Acute in vitro treatment with an inhibitor of arginase, 100μM N ω ‐hydroxy‐nor‐L‐arginine (Δ max 22±2μm) or the NOS substrate, 1mM L‐Arg restored flow‐induced dilation to unbled control levels (Δ max 17±1μm). In unbled controls, flow‐induced dilation was abolished by the NOS inhibitor, 1mM L‐NAME. These results suggest that arginase activity is increased following massive hemorrhage and contributes to endothelial dysfunction in resistance vessels by inhibiting endothelial NOS. Supported by NIH grants HL64577 (RAJ) and HL074966 (WD).