Oxidative degradation of bilirubin produces vasoactive compounds

Subarachnoid haemorrhage is often followed by haemolysis and concomitant ox idative stress, and is frequently complicated by pathological vasoconstrict ion or cerebral vasospasm. It is known that upregulation of haem oxygenase (HO-1) is induced by oxidative stress and results in release of biliverdin and bilirubin (BR), which are scavengers of reactive oxygen species (ROS). Here we report biomimetic studies aimed at modelling pathological condition s leading to oxidative degradation of BR. Oxidative degradation products of BR, formed by reaction with hydrogen peroxide (an ROS model system), demon strated biological activity by stimulating oxygen consumption and force dev elopment in vascular smooth muscle from porcine carotid artery. Analogous b iological activity was observed with vasoactive cerebrospinal fluid from su barachnoid haemorrhage patients. Three degradation products of BR were isol ated: two were assigned as isomeric monopyrrole (C9H11N2O2) derivatives, 4- methyl-5-oxo-3-vinyl-(1,5-dihydropyrrol-2-ylidene)acetamide and 3-methyl-5- oxo-4-vinyl-(1,5-dihydropyrrol-2-ylidene)acetamide and the third was 4-meth yl-3-vinylmaleimide (MVM), a previously isolated photodegradation product o f biliverdin. Possible mechanisms of oxidative degradation of BR are discus sed. Tentative assignment of these structures in the cerebrospinal fluid (C SF) of cerebral vasospasm patients has been made. It is proposed that one o r more of the degradation products of biliverdin or bilirubin are involved in complications such as vasospasm and or pathological vasoconstriction ass ociated with haemorrhage.