Role of nitric oxide and K+-channels in vascular hyporeactivity induced byendotoxin

This study was to investigate possible mechanisms associated with vascular hyporeactivity to vasoconstrictor agents in rats with endotoxaemia. Wistar- Kyoto rats were anaesthetised and injected with endotoxin [E. coli lipopoly saccharide (LPS), 10 mg/kg, i.v.] for 4 h. Pressor responses to noradrenali ne (NA, 1 mu g/lg, i.v.) were determined prior to and at every hour after L PS injection. After the in vivo experiment, rat thoracic aortas were excise d and prepared as rings 3-4 mm in width. The endothelium was mechanically r emoved to evaluate K+-channel activity and the effects of nitric oxide (NO) on the vascular smooth muscle. Our results demonstrated that (1) injection of LPS caused a significant fall in blood pressure and a severe vascular h yporeactivity to NA in the anaesthetised rat, (2) the relaxation induced by the K+-channel opener cromakalim was greater in rings obtained from endoto xaemic rats and this enhanced relaxation was partially inhibited by pretrea tment of these rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) , an inhibitor of the NO/cGMP pathway, (3) endotoxaemia for 3 h was also as sociated with a profound vascular hyporeactivity to NA ex vivo and this vas cular hyporesponsiveness was partially inhibited by ODQ, tetraethylammonium (TEA, a non-selective inhibitor of K+-channels) and charybdotoxin [CTX, a selective inhibitor of large conductance calcium-activated K+ channels (BKC a)], but not by apamin, and (4) the combination of TEA or CTX with ODQ comp letely restored that vascular responsiveness to normal. These results sugge st that activation of BKCa, and overproduction of NO in the vascular smooth muscle simultaneously contribute to vascular hyporeactivity to vasoconstri ctor agents in endotoxaemia.