Albumin Therapy Improves Local Vascular Dynamics in a Rat Model of Primary Microvascular Thrombosis

Abstract

Background and Purpose— High-dose human albumin is robustly neuroprotective in preclinical ischemia models and is currently in phase III clinical trial for acute ischemic stroke. To explore the hypothesis that albumin’s protective effect is mediated in part by salutary intravascular mechanisms, we assessed microvascular hemodynamics in a model of laser-induced cortical arteriolar thrombosis. Methods— The cortical microcirculation of anesthetized, physiologically monitored Sprague-Dawley rats was studied in vivo via a frontoparietal cranial window (intact dura) by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. Focal thrombosis was produced in 30- to 50-μm cortical arterioles by laser irradiation. Arteriolar flow velocity was measured repeatedly by line-scanning. At 30 minutes post-thrombosis, animals were treated with either human albumin, 2 g/kg, or with saline control. Results— Baseline arteriolar flow velocity averaged 3.5±1.8 mm/s and was reduced to 10% to 13% of control values by laser-induced thrombosis, which also led to focal vasodilatation (mean, 49% above baseline diameter). Saline treatment at 30 minutes post-thrombosis failed to influence arteriolar flow velocity, which remained depressed at 10% to 22% of control throughout the subsequent 60- to 90-minute observation period. By contrast, albumin treatment induced a prompt rise in median flow velocity to 38% of control by 10 minutes post-treatment, and to 61% to 67% of control by 50 to 60 minutes. Conclusions— High-dose albumin therapy induces a prompt, sustained improvement in microvascular hemodynamics distal to a cortical arteriolar thrombosis; these data support an important intravascular component to albumin’s protective effect in acute cerebral ischemia.

In Vivo Imaging of the Mouse Neurovascular Unit Under Chronic Cerebral Hypoperfusion

“…Specifically, we measured the slope of line scan images of pial arteries ( Figure 3A) and veins ( Figure 3B) to indicate inflow and outflow velocity, respectively, at each time point. 12 In the sham group, inflow velocity was not changed significantly throughout the entire observation period. In contrast, the inflow velocity after BCAS operation was significantly decreased when compared with those of preoperative baselines and sham controls ( Figure 3C).…”

Multifunctional Actions of Approved and Candidate Stroke Drugs

“…94,101 Intravascular mechanisms (e.g., reduced adherence of thrombotic material and an improved erythrocyte perfusion) may also contribute to a beneficial outcome. 95,102 Albumin mobilizes systemic fatty acids and may contribute to neural cell integrity post stroke by replenishing fatty acid lost from neural membranes during ischemia. 103,104 In addition, albumin was suggested to exert anti-inflammatory effects by binding the proinflammatory lysolipid lysophosphatidylcholine.…”

Albumin Therapy Augments the Effect of Thrombolysis on Local Vascular Dynamics in a Rat Model of Arteriolar Thrombosis

“…11 Using in vivo confocal microscopy in rats with middle cerebral artery occlusion, we showed that ALB reverses postischemic thrombotic phenomena in the venous microcirculation. 12 In a recent study using twophoton laser-scanning microscopy in vivo, 13 we validated a model of laser-induced focal cortical arteriolar thrombosis in the rat and demonstrated that ALB therapy leads to improved microvascular hemodynamics.…”

“…Positive evidence bearing on this issue, however, emerged from the ALIAS Pilot Clinical Stroke Trial, in which subjects who received thrombolysis (IV tissue plasminogen activator [tPA]) plus high-dose albumin were twice as likely to attain a favorable neurological outcome at 3 months as tPA-treated subjects who received lower-dose albumin therapy. 5 In the present report, we have extended our use of the model of laser-induced focal arteriolar thrombosis 13 in order to explore the microvascular pathophysiology of albumin therapy when combined with the thrombolytic agent, reteplase. Reteplase (Retavase, PDL BioPharma) is a nonglycosylated recombinant plasminogen activator variant derived from human tissue-type plasminogen activator and having a 4-fold longer half-life than tPA, permitting bolus injection.…”