Bilirubin and the induction of intracranial arterial spasm

Abstract

Although a number of substances which participate in the physiological control of vascular caliber have been proposed to play a causative role in cerebral vasospasm, none of these has been shown to induce the profound, sustained degree of constriction or the vasculopathy that characterize this disorder. The present study was undertaken to determine whether bilirubin, a hemoglobin breakdown product with detergent-like activity, accrued in incubated blood or in intracranial hematoma and whether topical application of bilirubin altered the caliber or morphology of cerebral arteries. As a model of blood residing in the subarachnoid space, sterile vials of cat blood and of human blood were incubated in vitro at 37 degrees C. The concentration of bilirubin in the supernatant of cat blood increased from a value of 0.27 +/- 0.3 mg% (mean +/- standard error of the mean) on Day 0 to a value of 9.57 +/- 2.4 mg% on Day 10; the respective values for human blood were 0.53 +/- 0.02 mg% and 13.4 +/- 5.4 mg%. Samples of intracranial hematoma that had been surgically removed from three patients between 4 and 11 days after hemorrhage yielded bilirubin levels from 2.1 to 15.2 mg%. Application of a bilirubin suspension of 5, 10, or 20 mg% in buffered Ringer's solution to cat basilar artery in vivo led to progressive and sustained constriction; at 4 hours the mean decrease in the width of the blood column was 34% +/- 2.1%. Ultrastructural analysis of these vessels showed widespread pathological changes similar to those associated with cerebral vasospasm. Application of a 10-mg% bilirubin suspension to the basilar artery of two baboons produced similar alterations. Minimal changes in diameter or morphology were observed in cat arteries bathed in buffer solution alone. These findings in animal models indicate that bilirubin may play a central role in the development of cerebral vasospasm.

Bilirubin oxidation products (BOXes): synthesis, stability and chemical characteristics

“…It is relatively well known that the spinal fluid of the subarachnoid haemorrhage patients was vasoactive and cytotoxic [2,10,37], but only recently were the BOXes reported in the haemorrhage patients' spinal fluid [38]. Interestingly, increased bilirubin in the spinal fluid of the subarachnoid haemorrhage patient has a time course that is similar to the reported incidence of vasospasm [8,47].…”

“…Bilirubin levels rise in the spinal fluid following subarachnoid haemorrhage [31] and their time course correlates well with the accepted time course of cerebral vasospasm, but bilirubin is not vasoactive. Thus there has been an interest in bilirubin's association with vasospasm, though with mixed results [3,4,8,9,27,28,30,32,38,47]. A bilirubin derivative such as BOXes is therefore quite consistent with the clinical characteristics of vasospasm.…”

Structural analysis of lipocalin-type prostaglandin D synthase complexed with biliverdin by small-angle X-ray scattering and multi-dimensional NMR

“…Our previous studies showed that the concentration of L-PGDS in CSF increased transiently in patients with SAH in the acute stage and suggested that the purified L-PGDS from the CSF of SAH patients bound bile pigments such as biliverdin and/or its analogs, the metabolites of hemoglobin (Inui et al, 2002;Mase et al, 1999). In addition, the oxidative degradation products of bilirubin and/or biliverdin are one of the causes inducing the delayed vasospasm in patients with SAH (Clark et al, 2002;Kranc et al, 2000;Duff et al, 1988). These lines of evidence suggest that L-PGDS is expected to be a scavenger of the bile pigments that accumulate in the CSF with SAH.…”

Bilirubin levels in subarachnoid clot and effects on canine arterial smooth muscle cells.

“…The weight of evidence suggests that the primary agents are derived from the hematoma itself1 and from the red blood cell in particular.2'3 In addition to extensive documentation of the vasoactivity of oxyhemoglobin,4-7 several reports have indicated that bilirubin, a hemoglobin breakdown product, is capable of producing constriction of cerebral arteries, both in vivo and in vitro. 4,8,9 One part of this study was undertaken to determine the levels of bilirubin in subarachnoid clot. The remainder of the study focused on the mechanisms of bilirubin-induced vasocontraction.…”