Cerebral vasospasm (CVS) is a life-threatening sequela for those who suffer subarachnoid hemorrhage (SAH). In its strict sense CVS consists of severe, sustained narrowing of the lumen of cerebral arteries and usually has its onset five to ten days after SAH. Morphological studies have shown major degenerative changes affecting all layers of the arterial wall. Because our preliminary studies have suggested that bilirubin plays a principal role in the development of CVs, we propose to investigate the following hypotheses: I. The vasoconstrictive and pathological effects of bilirubin on cerebral arteries are dose-, time-, and ph- dependent. These effects can be decreased by the presence of albumin. II. The vasoconstrictive and pathological effects of serum from 10 day incubated blood follow the same patterns of dose-, time-, and ph-dependence as those of bilirubin. These effects can also be decreased by the presence of albumin. III. The vasoconstrictive effect of bilirubin and of serum from 10 day incubated blood on smooth muscle cells is principally due to the induction of increased Ca2+ influx. The vasoconstriction can be decreased by low Ca2+ media, but the influx cannot be decreased by calcium channel blocking agents. IV. The catabolism of heme in clotted blood leads to the formation of IX alpha bilirubin, rather than to the formation of approximately equal percentages of the IX alpha, IX bata, IX gamma and IX delta isomers. Hypothesis V. The constrictive and pathological changes in basilar arteries following SAH can be reduced by delivery of albumin via an intra-arterial catheter. We will investigate Hypotheses I and II by measuring ultrastructural changes of cat basilar artery following in vivo application of bilirubin and of serum from incubated blood. Hypothesis III will be examined by contraction chamber measurement of contractile forces in media with both physiological and low levels of Ca2+ and by 45Ca2+ uptake studies on segments of cat basilar artery bathed in bilirubin and in serum from incubated blood. Hypothesis IV will be tested by HPLC analyst of bilirubin isomers formed in subarachnoid blood and in incubated blood. Hypothesis V will be investigated by quantitating angiographic changes following intra- arterial administration of albumin to animals previously subjected to subarachnoid hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020637-08
Application #
3401128
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-04-01
Project End
1993-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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