Chauhan, Sharmila Deepa; (2003) Endothelium-dependant dilatation - An investigation into the role of EDHF and the impact of sepsis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The endothelium plays a key role in the modulation of vascular tone. This is regulated in part, by the release of endothelium-derived relaxing factors, which include nitric oxide (NO), prostacyclin and endothelium derived hyperpolarising factor (EDHF). EDHF responses are characterised in the presence of a nitric oxide synthase inhibitor (NOS) and a cyclo-oxygenase inhibitor. Data from this thesis suggest that in the rat mesenteric artery there is a significant release of NO, despite the presence of a NOS inhibitor. This residual NO can be eliminated using an NO scavenger such as oxyhaemoglobin, in combination with a NOS inhibitor. The source of this NO is likely to be a photoactivatable endothelium derived NO store, and release of this NO contributes to the hyperpolarisation previously attributed to EDHF. C-type natriuretic peptide (CNP) is an endogenous vasodilator found in endothelial cells. In the perfused rat mesenteric bed, acetylcholine (ACh)-induced relaxation was associated with the release of CNP, in an endothelium-dependent fashion. CNP causes hyperpolarisation of vascular smooth muscle cells (VSMC) which is sensitive to the same K channel inhibitors as EDHF responses. Both ACh and CNP-induced relaxations were unaffected by the neuropeptide receptor (NPR) A and B antagonist HS-142-1, indicating that these responses were mediated through NPR-C. Inhibition of Gi protein using pertussis toxin also attenuated responses to ACh and CNP. The data suggest that CNP may be an EDHF in these tissues and mediates its effect through the NPR-C to cause hyperpolarisation of VSMC.Dysfunction of the endothelium is a marker for a variety of cardiovascular diseases including endotoxaemia. The final chapter investigated the effects of endotoxaemia on endothelial function using iNOS knockout (KO) and wild type (WT) mice. LPS pre-treatment suppressed responses to ACh and reduced sensitivity to Spermine-NO in arteries of WT mice. This effect was temporally associated with iNOS protein expression. In contrast arteries of iNOS KO animals did not exhibit any hyporeactivity to ACh or Sper-NO and did not express iNOS. These results clearly demonstrate that iNOS induction plays an integral role in mediation of the endothelial dysfunction associated with sepsis. Characterisation of EDHF responses in endotoxaemia revealed that these responses are upregulated in LPS-treated iNOS KO, endothelial NOS KO and WT mice, indicating an important role for EDHF in sepsis.

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