Vascular smooth muscle oxidative metabolism and function during vasospasm after subarachnoid haemorrhage

Thesis

Aims: The purpose of the research presented in this thesis is to elucidate the mechanism of the stimulation of oxidative metabolism and contractile function that occurs in vascular smooth muscle during cerebral vasospasm (CV) after subarachnoid haemorrhage (SAH). The biochemical mechanisms leading to CV were investigated using an in vitro model of CV developed for this research. CSF (cerebrospinal fluid) from SAH patients at risk of vasospasm which stimulated oxygen consumption (CSF S ) was used to model vasospasm. The hypothesis is CSF_S contains a substance which stimulates tension generation over that of CSF_N ,(non-stimulatory cerebrospinal fluid) and also inhibits the myosin light chain phosphatase.

Methods: The porcine carotid artery was used as a model for the human basilar artery. The rate of oxygen consumption (JO₂) was measured in response to CSF_S and tension generation was also examined. Various agents were used to treat or pretreat the tissue such as magnesium and andalpha;₁-adrenergic receptor agonists. Their effects on the CSF_S-induced stimulation were measured to study the mechanism of vasospasm. A myosin light chain phosphatase (MLCP) assay was developed to study the mechanisms leading to CV.

Results and conclusion: Addition of CSF_S to the porcine carotid artery is a reliable and reproducible in vitro model of CV. Using this model, it was found that Mg⁺⁺ loading and andalpha;₁-adrenergic receptor agonists attenuated the vasospasm, but a non-specific endothelin antagonist had no effect. Acute addition of 12mM Mg⁺⁺ relaxed the tissue from a CSF_S induced contraction significantly and rendered the contraction rinsible. Okadaic acid (InM), a phosphatase inhibitor, had very similar effects to CSF_S because it stimulated JO₂ and slowed relaxation after a stretch. There was also significant inhibition of phosphatase caused by the CSF_S. Vasospasm appears to be caused by a combination of a contractile stimulus, and inhibition of MLCP activity.

Authors: Pyne, G; Pyne, Gail Jean

• Publication date: 1999
• DOI: 10.5287/ora-doqkxaode
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Subarachnoid hemorrhage; Cerebrovascular spasm; Vascular smooth muscle