Effects of Bilirubin on Cerebral Arterial Tone in vitro

Abstract

Hemoglobin and its metabolite, bilirubin, have been shown to be present in high concentrations in CSF following subarachnoid hemorrhage (SAH). Several reports have indicated that hemoglobin is a potent cerebral vasoconstrictor and therefore is considered to be an active principle in the genesis of cerebral vasospasm. The possible role of bilirubin on the genesis of cerebral vasospasm, however, has not been clarified. The effect of bilirubin on cerebral vessel tone was therefore examined using in vitro tissue bath techniques. Bilirubin (10−5-3 × 10−5 M) induced strong constriction of cerebral arteries from the cat, dog, and pig. The vasoconstriction returned to baseline after bilirubin was washed by prewarmed Krebs solution. Vasomotor responses to various vasoactive substances were then examined after bilirubin was washed away (the bilirubin postwash effect). Norepinephrine (NE)–induced but not serotonin- or acetylcholine (ACh)–induced constrictions were significantly potentiated by bilirubin postwash effect. The potentiated NE-induced constriction was attenuated by yohimbine but not by prazosin. This enhanced vasoconstriction was mimicked by clonidine but not by phenylephrine, suggesting that the potentiation of NE-induced constriction by the bilirubin postwash effect was mediated by the α2-adrenoceptor subtype. The bilirubin postwash effect also resulted in blockade of endothelium-dependent vasodilations induced by A-23147, ACh, and ATP without affecting relaxations induced by direct muscle relaxants such as β-adrenoceptors, papaverine, and sodium nitroprusside. These results indicate that bilirubin induces direct vasoconstriction, potentiates α2-adrenoceptormediated vasoconstriction, and inhibits endothelium-dependent vasodilation. These actions of bilirubin may promote an enhanced overall vasoconstriction in vivo. Bilirubin, therefore, may be involved in the genesis of cerebral vasospasm following SAH.

Pharmacology and Physiology of Perivascular Nerves Regulating Vascular Function

“…Furthermore, the cerebral arterial smooth muscle of the large arteries at the base of the pig brain, which has been shown to contain mainly b1-adrenoceptors with fewer b 2-adrenoceptors and not significant a-adrenoceptors, relaxes exclusively upon application of exogenous NE (4,12,13). TNS of these isolated cerebral arteries exclusively elicited neurogenic vasodilation, a result similar to that found in the large cerebral arterial smooth muscle of the cat, which contains mainly a-adrenoceptors (1,14). This tetrodotoxin-sensitive vasodilation in large cerebral arteries of the pig and cat elicited by TNS was not affected by propranolol or guanethidine (1,4,12).…”

“…Similar results were found in isolated large cerebral arteries at the base of the cat brain that nicotine-induced vasodilation was sensitive to L-NNA (33). In these cerebral arteries of the cat, postsynaptic a-adrenoceptors are predominant, and exogenous NE induces a constriction exclusively (14,36). These findings clearly indicate that nicotine-induced vasodilation in the cat cerebral arteries can not be due to a direct effect of NE on the postsynaptic smooth muscle cells.…”

Bilirubin Production and Oxidation in CSF of Patients with Cerebral Vasospasm after Subarachnoid Hemorrhage

“…We have also suggested that bilirubin oxidation products, BOXes (Kranc et al, 2000) were found in the CSF of SAH patients and that these BOXes might contribute to vasospasm (Clark et al, 2002;Lyons et al, 2004). There are independent reports suggesting that oxidative stress (Cook, 1995;Macdonald and Weir, 1994;Watanabe et al, 1988;Weir, 1995) and bilirubin (Jia-Pei Miao and Jer-Fu Lee, 1989;Page et al, 1994) may correlate or contribute to vasospasm based on measurements in CSF (Page et al, 1994). But the thesis that oxidative stress leading to the oxidation of bilirubin (resulting in BOXes formation) as a contributing factor for vasospasm has been little studied.…”

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

“…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.…”