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 suggested that an excessive release of nitric oxide has a role in this hemodynamic derangement.


OBJECTIVE
To investigate whether inhibition of nitric oxide synthesis by the administration of N omega-nitro-L-arginine (LNNA), improves the vasoconstrictor effects of catecholamines in sepsis.


METHODS
Mechanically ventilated and pentobarbital-anesthetized 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 hour 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 micrograms, kg-1, min-1). Cardiovascular parameters were recorded at maximal blood pressure response achieved with each dose.


RESULTS
The administration of live E coli to the septic group resulted in systemic hypotension, high cardiac output, and hyperlactatemia. The LNNA caused a significant systemic and pulmonary vasoconstriction in both septic and nonseptic sheep. In nonseptic sheep, noradrenaline induced a significant increase 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 that received LNNA was nonsignificant (5,562 +/- 3,489 to 6,693 +/- 2,871 dyn, s, cm-5, m-2). Septic sheep showed a nonsignificant vasoconstriction 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 markedly 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 curve of systemic vascular resistance in these LNNA-pretreated septic sheep became very similar to the corresponding curve obtained in nonseptic animals.


CONCLUSIONS
Inhibition of nitric oxide synthesis by the administration of LNNA significantly improves the vasoconstrictor effect of noradrenaline in septic sheep, allowing an increase in systemic vasomotor tone similar to that observed in nonseptic sheep. It is concluded that increased synthesis of nitric oxide contributes to the depressed vascular reactivity to vasoconstrictor agents characteristic of sepsis.
Unidad de Cuidados Intensivos, Hospital Ramón y Cajal, Madrid, Spain.
L
L
Landín
J A
JA
Lorente
E
E
Renes
P
P
Cañas
P
P
Jorge
D
D
Liste
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004927:Escherichia coli Infections / Q000503:physiopathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019335:Nitroarginine; D009638:Norepinephrine / Q000494:pharmacology*; D012756:Sheep; D012772:Shock, Septic / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D009638:Norepinephrine