Variable effects of inhibiting iNOS and closing the vascular ATP-sensitive potassium channel (via its pore-forming and sulfonylurea receptor subunits) in endotoxic shock.
Excess production of NO and activation of vascular ATP-sensitive potassium (K(ATP)) channels are implicated in the hypotension and vascular hyporeactivity associated with endotoxic shock. Using a fluid-resuscitated endotoxic rat model, we compared the cardiovascular effects of an iNOS inhibitor and two distinct inhibitors of the K(ATP) channel. Endotoxin (LPS) was administered to anesthetized, spontaneously breathing, fluid-resuscitated adult male Wistar rats, in which MAP, aortic and renal blood flow, and hepatic microvascular oxygenation were monitored continuously. At 120 min, the iNOS inhibitor, GW273629, and the K(ATP)-channel inhibitors, PNU-37883A and glyburide, were administered separately, and their effects on hemodynamics and oxygenation were examined. We found that GW273629 increased MAP over and above the pressor effect achieved in sham animals. Inhibiting K(ATP) channels via the pore-forming subunit (PNU-37883A and high-dose glyburide) produced significant pressor effects, whereas inhibiting the sulfonylurea receptor with low-dose glyburide was ineffective. No agent reversed the fall in aortic or renal blood flow, the fall in hepatic microvascular oxygenation, or the metabolic acidosis that occurred in LPS-treated animals. We conclude that inhibition of the K(ATP) channel via the pore-forming, but not the sulfonylurea receptor subunit, increases blood pressure in a short-term endotoxic model. However, this was not accompanied by any improvement in macrocirculatory or microcirculatory organ blood flow nor reversal of metabolic acidosis. It therefore remains uncertain whether the iNOS pathway or the K(ATP) channel represents a potential target for drug development in the treatment of endotoxic shock.
O'Brien
Alastair
A
Department of Medicine, University College London, United Kingdom. a.o'brien@ucl.ac.uk
Stidwill
Raymond P
RP
Clapp
Lucie H
LH
Singer
Mervyn
M
D000818:Animals; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy; D013450:Sulfones / Q000494:pharmacology
C409003:GW 273629; D054086:KATP Channels; D008070:Lipopolysaccharides; D026902:Potassium Channel Blockers; D013450:Sulfones; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005905:Glyburide