Background: Septic shock is a serious clinical situation characterized by progressive hypotension with refractoriness to vasopressor proceeding to severe hemodynamic disturbances that lead to multiple system organ failure (MSOF) resulting in increased mortality. Objective: Study the role of nitric oxide (NO) signaling and K+- channels in the vascular hyporesponsivness to the vasopressors at early and late phases of the experimentally induced septic shock. Design: 54 Adult male Wistar albino rats were utilized in the present study. –In vivo experiment: Consisted of 30 animals which were subdivided equally into 5 groups; 1stgroup (Sham operated): Ceca were exposed, but without ligation or puncture. Animals were injected by vehicle intravenously(I.V); 2nd group (CLP): Rats were subjected to cecal ligation and puncture (CLP), and they were injected by vehicle I.V; 3rd group (L-NAME treated CLP): CLP rats treated with 100 mg /Kg of nitric oxide synthase inhibitor; { L- nitro Narginine methyl ester (L-NAME) }I.V; 4th group (MB treated CLP):CLP rats treated with 10 mg/Kg of soluble guanylylcyclase inhibitor{Methylene blue(MB)} S.C; 5th group (TEA treated CLP): CLP rats treated with 8mg/Kg of {Tetraethylammonium (TEA)}S.C .30 minutes after treatment with phosphate buffer saline(PBS); L- NAME; MB; TEA. Mean arterial pressure measurement, and dose response curves to PBS, and angiotensin II at 10, 20 & 30 Pmol/kg were obtained at 6 and 30 hrs postoperative. Blood samples were collected from sham and CLP operated rats at zero, 6 and/or 30 hrs after surgery to estimate the serum levels of AST, ALT, Creatinine, and Lactate as indicators for liver & kidney functions and acidosis respectively as well as for assessment of nitrate (NOx) levels. -In vitro experiment: 24 animals were prepared for isolation of aortic strips. The animals were subdivided into 2 main equal groups; 1stgroup: Sham operated (control): Animals were further subdivided equally and, sacrificed at time 6, and 30 hrs after sham operation; 2nd group (CLP): Animals were further subdivided equally, and sacrificed at times 6, and 30 hrs after CLP surgery. Vascular contractile response to norepinephrine (NE) was evaluated in both groups. Results: The present study revealed that LNAME, MB and TEA induced significant increases in MAP in vivo as well as increased contraction of isolated aortic strips in vitro upon exposure to increasing doses of the vasopressors angiotensin II & norepinephrine respectively in the late phase (30 hrs) of septic shock. Also, 2 1Elsayed M. Kamel et al., administration of the aforementioned compounds produced significant improvement in the biochemical indicators of liver and kidney impairment as well as lactate level, which were worsened by septic shock at the same point of time (30hrs). While they failed to produce these effects in the early phase (6 hrs) of septic shock. Conclusion: The nitric oxide signaling and K+- channels are crucial components implicated in the vasoplagia and vascular hyporesponesviness to the vasopressors in the late hypodynamic phase of septic shock. Moreover, they are involved in the consecutive tissue damage induced by long standing septic shock. So, NO pathway may constitute an attractive target for treatment of the late phase of this critical situation.