The Pathophysiologic Significance of Endothelins in the Cerebral Circulation

Patel, Toshal R (1996) The Pathophysiologic Significance of Endothelins in the Cerebral Circulation. PhD thesis, University of Glasgow.

Abstract

This thesis examined the pathophysiologic role of the endothelins in the cerebral circulation. Endothelin receptors were characterised in the rabbit basilar artery in vitro and in feline cerebral resistance arterioles in situ. Investigations in the feline cerebral resistance arterioles were designed to examine the cerebrovascular effects and blood-brain barrier penetration of non-peptide and peptide endothelin receptor antagonists. The pathophysiologic role of the endothelins were examined, using validated doses of endothelin receptor antagonists (primarily Bosentan), in experimental models of focal cerebral ischaemia in the cat, transient global cerebral ischaemia in the rat and subdural haematoma in the rat. In the rabbit basilar artery in vitro, pre-incubation with either the combined ETA/ETB endothelin receptor antagonist Bosentan (4-tert-Butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene sulphonamide) or the endothelin ETA receptor antagonist BQ-123 (cyclo D-Aspartate-D-Tryptophan-L-Leucine-D-Valine-L-Proline) had minimal effect on the resting tone of arterial segments. The ETB receptor agonist BQ-3020 (N-Acetyl [11 Ala,15 Ala] ET-1 (6-21)) elicited a small constriction of the arterial segments. Bosentan (10 muM) elicited a rightward shift of the ET-1 concentration response curve (pA2 = 5.1). BQ-123 (0.1 - 10 muM) elicited a concentration dependent rightward shift of the ET-1 concentration response curve (pA2 = 5.3). BQ-123 (1 muM) elicited a substantial rightward shift of the ET-3 concentration response curve (pA2 = 7.2). The observations suggested the presence of an 'atypical' endothelin ETA receptor mediating vasoconstriction in the rabbit basilar artery. The receptors mediating the cerebrovascular actions of endothelins were examined in feline cerebral resistance arterioles in vivo. The adventitial microapplication of the endothelin ETA receptor antagonist BQ-123 (0.1 - 10 muM) per se had minimal effect on cerebral resistance arterioles examined. The adventitial microapplication of endothelin-1 (10 nM) elicited a marked vasoconstriction of cerebral resistance arterioles (-29.1 +/- 1.9 % from pre-injection baseline). The endothelin-1 induced vasoconstriction was attenuated, in a dose dependent manner, by the adventitial co-application of BQ-123 and endothelin-1 (estimated IC50 0.7 muM). The adventitial microapplication of the endothelin ETB receptor agonist BQ-3020 (0.001 - 1 muM) effected a dose dependent vasodilatation (EC50 30 nM, maximum response 25 +/- 5 % from pre-injection baseline). The magnitude of the vasodilatation elicited by BQ-3020 (100 nM and 1 muM) was dependent on the pre-injection calibre of the arterioles examined. The intracarotid infusion (via the lingual artery) of BQ- 3020 (0.5-500 pmol/min) had no significant effect on the calibre of cerebral resistance arterioles. These results suggest that the peptide endothelin ETB receptor agonist fails to gain access to the cerebrovascular endothelin ETB receptors following its intraluminal administration. These investigations indicate that endothelin ETA receptors mediate vasoconstriction and endothelin ETB receptors mediate vasodilatation in feline cerebral resistance arterioles in vivo. The cerebrovascular actions of Bosentan, a novel endothelin antagonist with effects at ET.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: James McCulloch
• Keywords: Neurosciences
• Date of Award: 1996
• Depositing User: Enlighten Team
• Unique ID: glathesis:1996-74945
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 15:03
• Last Modified: 27 Sep 2019 15:03
• URI: https://theses.gla.ac.uk/id/eprint/74945