INHIBITION OF NITRIC-OXIDE SYNTHESIS IMPROVES THE VASOCONSTRICTIVE EFFECT OF NORADRENALINE IN SEPSIS

Background: Septic shock is characterized by systemic vasodilation and an impaired reactivity to vasoconstrictor agents. It has been suggest ed that an excessive release of nitric oxide has a role in this hemody namic derangement. Objective: To investigate whether inhibition of nit ric oxide synthesis by the administration of N-omega-nitro-L-arginine (LNNA), improves the vasoconstrictor effects of catecholamines in seps is. Material and Methods: Mechanically ventilated and pentobarbital-an esthetized sheep received either no treatment (n=6) or LNNA (100 mg/kg IV bolus, n=4). Other sheep (septic group) received live Escherichia coli (E coli) (1,5 10(9) micro-organisms/kg over 30 min) followed 1 h our later by either no treatment (n=5) or LNNA (100 mg/kg IV bolus, n= 7). After those interventions, all sheep were given noradrenaline in a continuous IV infusion at three different doses (0.5, 1.5, and 4.5 mu g, kg-1, min-1). Cardiovascular parameters were recorded at maximal b lood pressure response achieved with each dose. Results: The administr ation of live E coli to the septic group resulted in systemic hypotens ion, high cardiac output, and hyperlactatemia. The LNNA caused a signi ficant systemic and pulmonary vasoconstriction in both septic and nons eptic sheep. In nonseptic sheep, noradrenaline induced a significant i ncrease in systemic vascular resistance (from 2,973 +/- 637 to 4,561 = /- 1,287 dyn/s/cm(-5)/m(-2)), whereas the increase caused in those tha t received LNNA was nonsignificant (5,562 +/- 3,489 to 6,693 +/-,2,871 dyn, s, cm(-5), m(-2)). Septic sheep showed a nonsignificant vasocons triction during the infusion of noradrenaline (from 1,438 +/- 1,132 to 2,244 +/- 1,391 dyn/s/cm(-5)/m(-2)). However, treatment with LNNA mar kedly improved the vasoconstrictor effect of noradrenaline (from 2,804 +/- 2,317 to 4,894 -/+ 3,435 dyn/s/cm(-5)/m(-2)). The dose-response c urve of systemic vascular resistance in these LNNA-pretreated septic s heep became very similar to the corresponding curve obtained in nonsep tic animals. Conclusions: Inhibition of nitric oxide synthesis by the administration of LNNA significantly improves the vasoconstrictor effe ct of noradrenaline in septic sheep, allowing an increase in systemic vasomotor tone similar to that observed in nonseptic sheep. It is conc luded that increased synthesis of nitric oxide contributes to the depr essed vascular reactivity to vasoconstrictor agents characteristic of sepsis.