Background: An isolated arteriole fails to dilate in response to endotoxin unless a segment of aorta is included in the perfusion system. The unknown substance released by the aorta after exposure to endotoxin is dependent upon the NF-kappaB pathway and induces inducible nitric oxide synthase (iNOS) in the arteriole. The purpose of this study was to determine if cyclosporine A (CSA) that inhibits both NF-kappaB and iNOS would prevent the vasodilatory response to endotoxin.
Materials and methods: Rats were injected with either 10 mg/kg of CSA or oil vehicle followed by the removal of a cremaster muscle. The feeding arteriole was isolated from the cremaster and mounted on micropipettes and pressurized to 70 mmHg in a superfused tissue bath. After an hour equilibration to develop spontaneous tone, a 1 cm segment of aorta was placed in the superfusion system upstream from the arteriole and Salmonella enteriditis endotoxin was added to the buffer at a concentration of 2.5 microg/mL (ET) or continued infusion of buffer alone. Internal diameters of cannulated arterioles were measured with videomicroscopy and videocalipers for an additional hour.
Results: Arterioles downstream from an aorta exposed to vehicle but not endotoxin developed 22.8 +/- 3.7% tone that remained unchanged over the following hour. Arterioles exposed to endotoxin started with 22.5 +/- 2.8% spontaneous tone and this fell over the following hour to 11.8 +/- 3.6%, P < 0.05. Pre-treatment of the rats with CSA tended to increase resting tone and completely prevented the loss of tone after endotoxin.
Conclusions: Pre-treatment of the aortic segment with CSA resulted in the development of increased tone in the downstream arteriole and completely blocked the vasodilatory response to endotoxin. These results suggest that CSA or a similar compound may be useful in the treatment of septic shock.