Reduced vascular response to phenylephrine during exposure to lipopolysaccharide in vitro involves nitric oxide and endothelin 1.

Nitric oxide (NO) and endothelin 1 (ET-1) increase significantly during the first 4 h of Escherichia coli lipopolysaccharide (LPS) exposure. The aim of this study was to investigate the role of these mediators in the reduced response to phenylephrine treatment. We used male rat saphenous arteries (internal relaxed diameter, 63-152 microm; n = 48), mounted on a wire myograph and subsequently treated with LPS. At 1 h, LPS (dose, 50 microg mL(-1)) significantly (P < 0.05) inhibited constriction to phenylephrine (concentration, 10(-1)M to 10(-6)M) (LPS concentration required for half maximal response [EC50], 10.82 +/- 1.08microM; Control EC50, 5.07 +/- 0.34microM). However, by removing the endothelium (denuded) or adding Nomega-nitro-L-arginine methyl ester (L-NAME; concentration, 10(-4) microM), the response to phenylephrine treatment was significantly improved compared with LPS only-treated arteries (LPS + denuded EC50, 7.04 +/- 1.12microM; LPS + L-NAME EC50, 2.64 +/- 0.63microM). On the other hand, denudation did not restore constriction to phenylephrine at 2 and 4 h. However, L-NAME and the nonspecific ET-1 receptor antagonist bosentan (concentration, 10(-5)M) improved constriction to phenylephrine in LPS-treated arteries (P < 0.05) at 4 h (LPS EC50, 998.50 +/- 447.10microM; LPS + L-NAME EC50, 65.23 +/- 25.61microM; LPS + bosentan EC50, 63.65 +/- 25.33microM). We conclude that endothelium-dependent mechanisms have an early role in the reduced responsiveness of vascular smooth muscle to vasoconstrictors during simulated septic conditions. Shortly after exposure to LPS (duration, 1 h), endothelium-derived NO seemed to have a role in reduced arterial constriction to phenylephrine, but later (4 h) ET-1 and endothelium-independent increase in NO seemed to contribute further to the loss of response.