1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response.