Chan, Y.-L.; (2011) The role of the vascular KATP channel in septic models. Doctoral thesis , UCL (University College London).

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Abstract

Septic shock is characterized by systemic vasodilatation and an attenuated pressor response to catecholamines. As the hyperactivity (i.e. more channels remain in the open state) of the vascular adenosine triphosphate (ATP)- sensitive type of potassium (KATP) channels results in vasodilatation, this channel has been implicated in the pathogenesis of septic shock. The studies present in this thesis sought to demonstrate that sepsis activates vascular KATP channels, that channel inhibition reverses hypotension, and that channel hyperactivity is related to an increased gene expression. Rat aortic smooth muscle cells exposed to bacterial endotoxin and the inflammatory mediator interleukin-1β were found to have an increased gene expression of KIR6.1, the channel’s pore-forming subunit, at 48h. This gene induction could be reversed by the nitric oxide synthase inhibitor, 1400W. KIR6.1 mRNA was also increased in mesenteric arteries from rats subjected to faecal peritonitis for 24h. 86Rubidium efflux experiments revealed an increased channel activity in these vessels when stimulated by the KATP-channel opener, levcromakalim; the basal activity, however, remained unchanged. Conscious rats subjected to faecal peritonitis developed an attenuated pressor response to norepinephrine that, unexpectedly, could not be reversed by the channel inhibitor, PNU-37883A; this agent could not either elevate the baseline blood pressure of septic rats. Surprisingly, this attenuated pressor response to PNU-37883A could be partially reversed by the autonomic ganglion blocker, pentolinium, suggesting that during sepsis the vascular KATP channel may be inhibited in vivo by the high sympathetic tone. Therefore, the inhibition of vascular KATP channels may assume a limited role in the treatment of septic shock.

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