Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats.
OBJECTIVE
Acute cerebral hypoperfusion and early disturbances in cerebral autoregulation after subarachnoid hemorrhage (SAH) have been demonstrated repeatedly and have been shown to contribute significantly to acute and secondary brain injury. Acute vasoconstriction has been identified as a major contributing factor. Although increasing evidence implicates endothelin (ET)-1 in the development of cerebral vasospasm, its role in the acute phase after SAH has not yet been investigated. The purpose of this study was to further determine the role of ET in the first minutes to hours after massive experimental SAH induced by prophylactic treatment with the ET receptor antagonist clazosentan.


METHODS
Subarachnoid hemorrhage was induced in 22 anesthetized rats by injection of 0.5-ml arterial, nonheparinized blood into the cisterna magna over the course of 60 seconds. In addition to monitoring intracranial pressure (ICP) and mean arterial blood pressure, laser Doppler flowmetry (LDF) probes were placed stereotactically over the cranial windows to allow online recording of cerebral blood flow (CBF) starting 30 minutes prior to SAH and continuing for 3 hours after SAH. The control group (Group A, 11 rats) received vehicle saline solution via a femoral catheter before SAH, and a second group (Group B, 11 rats) was treated prophylactically with clazosentan, an ET(A) receptor antagonist. Treatment was started 30 minutes prior to bolus injection (1 mg/kg body weight), immediately followed by a continuous infusion of 1 mg/kg body weight/hr until the end of the experiment.


RESULTS
Induction of SAH in the rats caused an immediate increase in ICP, which led to an acute decrease in cerebral perfusion pressure (CPP). Perfusion, as measured with LDF, was found to have decreased relative to baseline by 30 +/-20% in the control group and 20 +/-9% in the clazosentan-treated group. Intracranial pressure and CPP recovered comparably in both groups thereafter within minutes. Control animals demonstrated prolonged hypoperfusion with a loss of autoregulation independent of CPP changes, finally approaching 80% of baseline values toward the end of the experiment. The authors observed that clazosentan did not influence peracute CPP-dependent hypoperfusion, but prevented continuous CBF reduction. Laser Doppler flowmetry perfusion readings remained depressed in control animals at 73 +/-19% of baseline in comparison with 106 +/-25% of baseline in clazosentan-treated animals (p = 0.001).


CONCLUSIONS
The first hours after a massive experimental SAH can be characterized by a CPP-independent compromise in cerebral perfusion. Prophylactic treatment with the ET receptor antagonist clazosentan prevented hypoperfusion. It is known that in the first days after SAH, a reduction in CBF correlates clinically to high-grade SAH. Although research currently focuses on delayed vasospasm, administration of vasoactive drugs in the acute phase of SAH may reverse perfusion deficits and improve patient recovery.
Schubert
Gerrit A
GA
Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. gerrit.schubert@nch.ma.uni-heidelberg.de
Schilling
Lothar
L
Thomé
Claudius
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D017078:Laser-Doppler Flowmetry; D008297:Male; D023421:Models, Animal; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology* / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000503:physiopathology / Q000517:prevention & control
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan