Involvement of thrombolysis in recombinant tissue plasminogen activator-induced cerebral hemorrhages and effect on infarct volume and postischemic endothelial function.
OBJECTIVE
In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function.


METHODS
Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR.


RESULTS
No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8+/-2.3 petechiae versus 3.0+/-1.0 petechiae in rtPA group; P<0.001). This increased severity was associated with a significant increase of both infarct volume (182+/-10 versus 144+/-15 mm3 in rtPA group; P<0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9+/-0.5% versus 13+/-1% in rtPA group; P<0.05).


CONCLUSIONS
Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.
Gautier
Sophie
S
Laboratoire de Pharmacologie, Faculté de Médecine, Lille, France. bordet@univ-lille2.fr
Petrault
Olivier
O
Gele
Patrick
P
Laprais
Maud
M
Bastide
Michelle
M
Bauters
Anne
A
Deplanque
Dominique
D
Jude
Brigitte
B
Caron
Jacques
J
Bordet
Régis
R
D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology; D005341:Fibrinolysin / Q000494:pharmacology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology; D015996:Survival Rate; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
D005338:Fibrin Fibrinogen Degradation Products; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin