Albumin therapy augments the effect of thrombolysis on local vascular dynamics in a rat model of arteriolar thrombosis: a two-photon laser-scanning microscopy study.
OBJECTIVE
Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis.


METHODS
We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30- to 50-microm cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control.


RESULTS
Baseline arteriolar flow velocity averaged 3.8+/-0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (P=nonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (P=0.013 versus reteplase+saline), which remained significantly higher than the reteplase+saline group at multiple time-points over the subsequent hour.


CONCLUSIONS
The beneficial effect of subthrombolytic doses of reteplase on microvascular hemodynamics distal to a cortical arteriolar thrombosis is markedly enhanced by the coadministration of high-dose albumin therapy; these results have important clinical implications for the management of patients with acute ischemic stroke.
Park
Hee-Pyoung
HP
Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami Miller School of Medicine, PO Box 016960, Miami, FL 33101, USA.
Nimmagadda
Anitha
A
DeFazio
Richard A
RA
Busto
Raul
R
Prado
Ricardo
R
Ginsberg
Myron D
MD
D000418:Albumins / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D020767:Intracranial Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D007834:Lasers / Q000009:adverse effects; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D000418:Albumins; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C087896:reteplase; D010959:Tissue Plasminogen Activator