ENDOTOXIN INTERACTS WITH TUMOR-NECROSIS-FACTOR-ALPHA TO INDUCE VASODILATION OF ISOLATED RAT SKELETAL-MUSCLE ARTERIOLES

Sepsis is characterized by decreased peripheral vascular resistance, h owever, discrepancies exist regarding the specific secondary mediators involved. This study examined whether the presence of endotoxin (ET) is a requirement for tumor necrosis factor-alpha (TNF-alpha) to induce vasodilation of isolated skeletal muscle arterioles. First order crem asteric arterioles were isolated from male Sprague-Dawley rats, cannul ated with glass micropipettes, superfused in physiologic saline, and a llowed to achieve spontaneous basal tone in the absence of intralumina l flow. A2 min exposure to TNF-alpha (.01-100 ng/ml) had no apparent e ffect on arteriolar diameter (95 +/- 5% after .01 ng/mL and 92 +/- 6% after 100 ng/mL, p >.05 compared with basal). However, arterioles supe rfused with 2.5 mu g/mL Salmonella enteritidis ET for 1 h followed by a 2 min exposure to 100 ng/mL TNF-alpha demonstrated a dilation (to 12 8 +/- 12%) that became statistically significant 10 min after TNF-alph a washout (to 142 +/- 12%, p <.05). This effect was eliminated by comb ined inhibition of cycooxygenase (with indomethacin) and nitric oxide synthase (L-NAME). The data indicate that neither ET or TNF-alpha alon e elicit a direct vasomotor effect on the isolated arteriole preparati on used in these studies. However, pretreatment of the vessels with ET results in the ability of TNF-alpha to cause arteriolar dilation, pos sibly through a mechanism involving both cyclooxygenase and nitric oxi de synthase.