The present study was carried out on mesenteric vascular bed from LPS-injected rats in order to investigate the cause of hyporesponsiveness in resistance blood vessels, during septic shock syndrome. The involvement of L-Arg/NO pathway was evaluated by administration of L-Arg, which produced a decrease in perfusion pressure in LPS-treated rats, whereas it was ineffective in control rats. Furthermore, DEX-pretreatment in endotoxaemic rats significantly reduced the vasorelaxation by L-Arg, whereas it was ineffective to reverse vascular hyporeactivity occurring in septic shock. In order to evaluate whether hyporesponsiveness could be due to defects in contraction mechanisms, we tested the effect of ET-I. This peptide was able to markedly enhance the contractile response to NA in LPS-treated rats. Our findings suggest that vascular hyporesponsiveness during septic shock may depend on both activation of the L-Arg/NO pathway and alterations in post-receptor mechanisms involving calcium handling.