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

Abstract

Previous studies have suggested that bilirubin is a potential contributor to cerebral vasospasm. The purpose of this investigation was to determine whether bilirubin accrues in subarachnoid clot, whether its vasoconstrictive effect could involve a direct action on arterial smooth muscle cells, and, if so, whether bilirubin affects their Ca2+ uptake. Subarachnoid clots were analyzed for bilirubin using high-performance liquid chromatography. The length and 45Ca2+ uptake of vascular smooth muscle cells enzymatically dissociated from canine carotid arteries were measured before and after exposure to bilirubin solution. Additional experiments were conducted on cultured smooth muscle cells from canine basilar artery and on ATP-depleted cardiac myocytes. Mean +/- SE bilirubin concentration in experimental clot was 263 +/- 35.7 mumol/L. Vascular smooth muscle cells exposed to bilirubin showed progressive shortening (P < .01) and an increased uptake of 45Ca2+ (P < .001). Contraction was prevented by Ca(2+)-free media but not by verapamil. Experiments with heart myocytes showed that bilirubin caused an increased uptake of 45Ca2+ but not of [14C]sucrose. The results indicate that bilirubin accrues in subarachnoid clot, that it exerts a direct constrictive effect on arterial smooth muscle cells, and that this effect is associated with an increased uptake of Ca2+. Studies on heart myocytes suggest that the Ca2+ uptake induced by bilirubin could be due to a selective increase in membrane permeability to Ca2+.

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.…”

Hyperbilirubinemia modulates myocardial function, aortic ejection, and ischemic stress resistance in the Gunn rat

“…The Ca 2ϩ -binding properties of bilirubin itself (11) provide extra-and intracellular Ca 2ϩ sinks, while the reduced expression of parvalbumin reported in Gunn rats (albeit for neuronal tissue) (28) could limit contractility if arising in the myocardium. On the other hand, bilirubin can increase smooth muscle permeability to Ca 2ϩ (32). Antioxidant actions of bilirubin might also modify redox-dependent control of contraction (31), whereas Malik et al (17) have shown that bilirubin negatively influences mitochondrial energy production, thus potentially energy-dependent contraction.…”

Oxidative degradation of bilirubin produces vasoactive compounds

“…Due to its antioxidant activity BR can serve as a protective agent in cells, membrane lipids and low‐density lipoproteins (LDL) exposed to oxidative stress [5–8]. High levels of BR are found in clots in the perivascular area and in CSF following SAH (CSF SAH ; cerebrospinal fluid from subarachnoid haemorrhage patients) [9,10].…”

“…There have been extensive studies searching for the vasoactive compounds in the CSF of SAH patients [1–6,9–11,14]. Bilirubin had been implicated but never shown to be the cause of cerebral vasospasm.…”