Propentdyopents as Heme Degradation Intermediates Constrict Mouse Cerebral Arterioles and Are Present in the Cerebrospinal Fluid of Patients With Subarachnoid Hemorrhage.

RATIONALE: Delayed ischemic neurological deficit is the most common cause of neurological impairment and unfavorable prognosis in subarachnoid hemorrhage (SAH) patients. Despite the existence of neuroimaging modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed perfusion deficit. Previous studies have suggested that bilirubin oxidation products (BOXes), originating from released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction. Recently, isolated intermediates of oxidative bilirubin degradation, known as propentdyopents (PDPs), have been considered as potential additional effectors in the development of arterial vasoconstriction.

OBJECTIVE: To investigate whether PDPs and BOXes are present in hemorrhagic cerebrospinal fluid (CSF) and involved in the vasoconstriction of cerebral arterioles.

METHODS AND RESULTS: Via liquid chromatography/mass spectrometry, we measured increased PDP and BOX concentrations in CSF of SAH patients compared to control subjects. Using differential interference contrast microscopy, we analyzed the vasoactivity of PDP isomers in vitro by monitoring the arteriolar diameter in mouse acute brain slices. We found an arteriolar constriction upon application of PDPs in the concentration range that occurs in the CSF of SAH patients. By imaging arteriolar diameter changes using 2-photon microscopy in vivo, we demonstrated a short onset vasoconstriction after intrathecal injection of either PDPs or BOXes. Using MRI, we observed a long-term PDP-induced delay in cerebral perfusion. For all conditions, the arteriolar narrowing was dependent on functional BKCa channels and was absent in BKCa knockout mice.

CONCLUSIONS: For the first time, we have quantified significantly higher concentrations of PDP and BOX isomers in the CSF of SAH patients compared to controls. The vasoconstrictive effect caused by PDPs in vitro and in vivo suggests a hitherto unrecognized pathway contributing to the pathogenesis of delayed ischemic deficit in SAH patients.