Effects of N-Acetyl-L-Cysteine and Hyaluronic Acid on HBOC-201- Induced Systemic and Cerebral Vasoconstriction in the Rat

Abstract

Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.

Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact

“…but this change occurred equally in both test and control groups. This vasoconstriction was similar to results from another study in salinetreated rats (Abutarboush et al, 2013) and suggests the effects may be related to surgical preparation of the model, anesthesia, intra-cranial pressure changes, or surface temperature changes in the exposed brain. Nonetheless, vasoconstriction after topical BaCl 2 application at the end of the study confirmed the responsiveness and viability of the vessels.…”

“…Pial arteriolar diameters were measured at the same locus throughout the experiment using the computer program CellSens (Olympus, 2010). Similar to previous cerebrovascular studies (Abutarboush et al, 2013;Rebel et al, 2006;Rebel et al, 2003), the pial arteriolar vessel diameters were divided into three categories based on size at baseline measurement: (1) "small" vessels having a diameter b 50 μm, (2) "medium" vessels with diameters of 50 to 100 μm, and (3) "large" vessels with diameters N 100 μm. The division into size categories was based on the fact that the amount of smooth muscle increases with vessel size which could lead to differences in degree of vessel contraction (Rosenblum, 1976).…”

Cerebral Microvascular and Systemic Effects Following Intravenous Administration of the Perfluorocarbon Emulsion Perftoran

“…HR was significantly different among the groups at baseline (T0) but was still within the normal range for rats under the anesthesia regimen used in this study [13,14,15,16,17] and did not exhibit any cumulative change (comparing T0 to T150) over time within any of the groups (Table 1). The only significant change in HR after an individual infusion was a slight transient increase in the 0.9% NaCl group after the third infusion.…”

Cerebral Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats

“…18,19 A stereomicroscope (SZ16, Olympus, Japan) equipped with a DP-73 digital camera was used for direct visualization and imaging of pial vessels at 80X. Arteriole sizes were divided into three categories for analysis of microvessel measurements: small (<50 µ m), medium (50-100 µ m), and large-sized (>100 µ m) vessels.…”

“…Grouping the vessels into these categories is the convention in the microvascular literature 19,23 and is scientifically justified since the amount of smooth muscle increases with vessel size and the degree of contraction correlates with the amount of vascular smooth muscle. 24 6…”