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Title: Regulation of vascular ATP-sensitive potassium channels by calcium and inflammatory mediators
Author: Wilson, Andrew James
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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In the vasculature, ATP-sensitive K+ (KATP) channels are targets for hormones, which modulate channel activity via phosphorylation. Vasodilator hormones, like adenosine, are known to activate KATP current, whilst vasoconstrictors, such as angiotensin II, inhibit KATP current. Since these hormones also modulate intracellular Ca2+ ([Ca2+]i), it is conceivable that regulation of the channel by these agents might occur through a Ca2+-sensitive pathway, although this has not been directly investigated. Using the patch-damp technique, increases in [Ca2+]i, inhibited whole-cell KATP current in isolated rat aortic smooth muscle cells, an effect reversed by inhibitors of the Ca2+-dependent protein phosphatase, calcineurin. Regulation of KATP current was steeply dependent on [Ca2+]i within the physiological range (100-300 nM). Thus, hormonal regulation of KATP channels might occur via regulation of calcineurin activity. KATP channels have also been implicated as a target for the vasodilator, nitric oxide (NO). Endotoxic shock, a severe condition that occurs following exposure to bacterial lipopolysaccharide (LPS), is characterised by induction of NO synthase (iNOS) and profound vasodilation. Under these conditions, NO production is known to be excessive, so it is likely that abnormal activation of KATP channels will result. In organ bath experiments, relaxation of LPS-treated rat aortic rings to the iNOS substrate, L-arginine, was sensitive to a variety of K+ channel inhibitors. Pharmacological characterisation of this response revealed that KATP channels are likely to contribute to relaxation, although only inhibitors that directly interacted with the channel pore, were effective, whereas agents which bind to the sulphonylurea subunit, were without effect. In contrast, relaxation evoked by exogenously applied NO was only weakly affected by K+ channel inhibitors. These data suggest that the regulation of KATP channels become deranged in endotoxic shock, and indicate that inhibitors of the KATP channel pore may be more effective agents to probe KATP channel function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine