Blood loss induces heme oxygenase‐mediated carbon monoxide formation to promote endothelial dysfunction in rat arterioles

Abstract

Acute blood loss triggers heightened vasoconstriction which contributes to maintenance of the blood pressure. Hemorrhage also induces shock proteins, including heme oxygenase (HO)-1. HO metabolizes heme to form carbon monoxide (CO), which inhibits nitric oxide synthase to promote endothelial dysfunction. This study examines the hypothesis that hemorrhage induces HO-1, to enhance CO production and promote endothelial dysfunction which contributes to the restoration of blood pressure. Male Sprague-Dawley rats (300-350g) with chronic femoral arterial catheters were subjected to a 45% hemorrhage (shock). Hemorrhage produced vasodepression from 117±2 mmHg to 78±6 mmHg in 1 hour. At 36hrs, vascular HO-1 was induced (shock: 2.7±0.3 vs unbled: 1.1±0.2 ng/mg Pr), which was accompanied by a 25% increase in expired CO and restoration of arterial pressures to 106±2 mmHg. First order gracilis muscle arterioles, isolated from each group, were mounted in a microvessel chamber, superfused with oxygenated Krebs buffer and exposed to constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow (0-50μL/min). Flow-induced dilation was abolished in shock arterioles (Δmax 0±0μm vs Δmax18±1μm, shock vs unbled; P<0.05). Acute pretreatment with an inhibitor of HO, chromium mesoporphyrin (15μmol/L) restored flow-induced dilation to control levels (Δmax 30±1μm). These data show that hemorrhagic shock can induce HO-1 to increase CO formation and promote endothelial dysfunction. Accordingly it suggests that shock induced increases in CO formation may contribute to the restoration of blood pressure via its well established ability to inhibit nitric oxide synthase. Supported by NIH/NHLBI R01 grant 64577