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Excerpt
Nitric oxide (NO), a potent endogenous vasodilator, has been implicated in vascular relaxation and hypotension in sepsis [1]. NO relaxes vascular smooth muscle by activating soluble guanylate cyclase and increasing intracellular cyclic guanosine 3[prime],5[prime]-cyclic monophosphate. The enzyme nitric oxide synthase (NOS), which synthesizes NO from endogenous L-arginine, has several isoforms, each encoded by a distinct gene [2]. The constitutive isoform is present in endothelial cells, is regulated by calcium released after the binding of agonists to receptors, and synthesizes relatively small amounts of NO within seconds. The role of the constitutive isoform is rapid servoregulation of vascular tone [2]. Inducible NOS isoforms are present in many cell types, including macrophages, hepatocytes, and vascular smooth muscle cells. Regulated at the transcriptional level, inducible NOS is calcium-independent and releases large amounts of NO in a sustained fashion, after stimulation with mediators associated with sepsis such as endotoxin, tumor necrosis factor, interleukin-1, interleukin-2, and interferon-gamma [2]. This immunologically induced, sustained release of NO may have evolved as an antimicrobial defense, but the large amounts of NO released by inducible NOS can have marked effects on both vascular tone and permeability. Septic patients have evidence of increased NO production in that urine concentrations of nitrate and nitrite, the stable end-products of NO oxidation, are increased [3].
Production of NO by both NOS isoforms can be inhibited in a competitive fashion by analogs of L-arginine, such as NG-methyl-L-arginine, Nomega-nitro-L-arginine (L-NNA), and Nomega-nitro-L-arginine methyl ester (L-NAME). Accordingly, NOS inhibition using these agents is a logical strategy in the treatment of septic patients with pressor-dependent hypotension. NOS inhibitors would be expected to have a more marked effect on the vessels with the greatest production of NO, giving them theoretical advantages over other vasopressors that constrict all vessels equally [4].
Evidence from animal models has suggested that NOS inhibitors can improve blood pressure and increase systemic vascular resistance [5,6]. This increased blood pressure, however, may come at a price. In a porcine model of endotoxemia, NOS inhibition with L-NAME, given as a continuous infusion, decreased cardiac output and exacerbated the increase in pulmonary arterial pressures seen in this model [7]. Similar findings are evident after short-term administration of NOS inhibitors to septic patients. Petros et al. [8] gave the NOS inhibitor NG-methyl-L-arginine to 12 patients with septic shock requiring pressor therapy and obtained an increase in mean arterial pressure (MAP) from 81 to 101 mm Hg, with a decrease in cardiac output from 11.2 to 8.9 L/min and an increase in pulmonary vascular resistance from 122 to 238 dyne[center dot]sec/cm5. Lorente et al. [9] found a similar pattern after bolus infusion of L-NNA to eight patients with sepsis syndrome, with an increase in MAP of 57%, a decrease in cardiac output of 24%, and an increase in pulmonary vascular resistance of 53%.
In this context, the study by Dr. Avontuur and colleagues [10] in this issue of Critical Care Medicine is of interest because it demonstrates the hemodynamic effects of prolonged NOS infusion in pressor-dependent septic patients. A 12-hr infusion of L-NAME at 1 mg/kg/hr increased MAP from 65 to 93 mm Hg, and decreased cardiac output by 19%, resulting in an increase in systemic vascular resistance of 64%. Pulmonary arterial pressure increased from 31 to 36 mm Hg, which, along with the decreased cardiac output, produced an increase in pulmonary vascular resistance of 44%. The hemodynamic effects of L-NAME did tend to diminish over the 12-hr study period, although these effects were sustained during prolonged administration. The study by Dr.
