PDTC and MG132, Inhibitors of NF-??B, Block Endotoxin Induced Vasodilation of Isolated Rat Skeletal Muscle Arterioles

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Abstract
NF-kappaB is a ubiquitous transcription factor that mediates the inflammatory response. Inhibition of NF-kappaB may be of potential therapeutic benefit in the treatment of septic shock. The antioxidant pyrrolidine dithiocarbamate (PDTC) has been shown in previous work to selectively inhibit NF-kappaB activation. Likewise, the proteasome inhibitor MG132 inhibits NF-kappaB formation and degradation of its inhibitor I-kappaB. The goal of this study was to determine if PDTC and MG-132 could inhibit resistance arteriole vasodilation in response to endotoxin and to determine PDTC's site of action in our isolated vessel preparation. Male Sprague-Dawley rats were given an intraperitoneal injection of PDTC, an intravenous injection of MG132, or a sham injection. First-order cremasteric arterioles were isolated, cannulated, and pressurized. A segment of thoracic aorta was then placed in series with the microvascular preparation. Vessels were allowed to achieve spontaneous myogenic tone in a bath of buffer over 1 h (t = 0). Internal vessel diameters were measured and the response to endotoxin (ET) or continued infusion of buffer was measured over 1 h (t = 60). Group 1 (n = 7) was a time-control group. Group 2 (n = 7) was exposed to ET only, Group 3 (n = 5) received PDTC and was exposed to ET, Group 4 (n = 5) received PDTC only, Group 5 (n = 4) received MG132 only, and Group 6 (n = 5) received MG132 and was exposed to ET. To determine the site of action of PDTC, a segment of aorta from an animal treated with PDTC was placed in series with a cremasteric arteriole from an animal receiving a sham injection. The preparation was then exposed to ET, and this is Group 7 (n = 4). Group 8 (n = 4) received ET and was composed of thoracic aorta from an animal receiving a sham injection and a cremasteric arteriole from a PDTC-treated animal. Spontaneous tone was similar in the eight groups at the end of the equilibration period (t = 0). After 1 h (t = 60), Group 2 (vessels exposed to ET only) had significantly less tone (26.1%+/-2.6%; P < 0.01) than Group 1 (39.0%+/-2.4%), Group 3 (39.3%+/-3.1%), Group 4 (41.2%+/-1.6%), Group 5 (39.2%+/-2.9%), Group 6 (41.0%+/-2.7%), Group 7 (45.1%+/-6.5%), and Group 8 (41.1%+/-4.5%). We conclude that PDTC and MG132, inhibitors of NF-kappaB, block ET-induced vasodilation in isolated rat skeletal muscle arterioles. PDTC has effects at both the level of the aortic segment as well as the resistance arteriole. Inhibitors of NF-kappaB may potentially be of therapeutic benefit in the treatment of septic shock.