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Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock
Soni Savai Pullamsetti1, Daniel Maring, Hossein Ardeschir Ghofrani
1Departmennt of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392 Giessen, Germany.
Abstract:
Treatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To compare the effects of epinephrine titration, non-selective NOS inhibition by L-NMMA and selective inhibition of inducible NOS (iNOS) by 1400W on hemodynamics and on the regulation of microcirculation in a rat model of endotoxic shock, we intravenously injected endotoxin (LPS) or saline to male Wistar rats and after 2 hours randomized LPS treated rats into four different groups that received either saline, norepinephrine, L-NMMA or 1400W (n = 6 per group). Three hours after LPS administration, rats presented with severe systemic arterial hypotension (64 +/- 3 vs. 115 +/- 4 mmHg, p < 0.001), unresponsiveness to volume treatment, lactate acidosis and a marked increase in plasmatic nitrite and nitrate levels (15 +/- 8 vs. 263 +/- 47 microM, p < 0.001). Measurement of the tissue oxygenation in the ileum mucosal layer by the Erlangen micro-lightguide spectrophotometer (EMPHO) technique demonstrated marked heterogeneity of hemoglobin saturation, with appearance of low oxygenated areas. Norepinephrine, usually stabilizing blood pressure (99 +/- 7 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.01), increased lactate formation (7.9 +/- 0.2 vs. 3.7 +/- 0.5 mM, p < 0.001) and drastically increased low oxygenated regions in the ileum mucosal layer. L-NMMA similarly increased blood pressure (92 +/- 6 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.05), but did not enhance lactate acidosis. However, some further deterioration of mucosa oxygenation was again noted. 1400W forwarded stabilization of blood pressure (88 +/- 5 vs. 67 +/- 4 mmHg 60 min after injection, p < 0.05), reduced plasmatic nitrite and nitrate levels similar to L-NMMA, without an aggravation of lactate acidosis. In addition, mucosal oxygenation did not deteriorate in response to this agent. Thereby, we conclude that in a rat model of endotoxic shock selective iNOS inhibitors are superior to non-specific NOS inhibitors and in particular to norepinephrine for the treatment of macro- and microcirculatory abnormalities in experimental septic shock.
Insights
Selective inducible nitric oxide synthase (iNOS) inhibitors effectively treat septic shock by improving hemodynamics and microcirculation, outperforming non-selective inhibitors and norepinephrine in a rat model.
Area of Science:
- Physiology
- Pharmacology
- Critical Care Medicine
Background:
- Septic shock causes hemodynamic instability and microcirculatory dysfunction.
- Vasopressors can worsen microcirculation, while nitric oxide synthase (NOS) inhibition is a potential alternative.
- Excessive nitric oxide (NO) production is implicated in sepsis pathophysiology.
Purpose of the Study:
- To compare the effects of norepinephrine, non-selective NOS inhibition (L-NMMA), and selective inducible NOS (iNOS) inhibition (1400W) on hemodynamics and microcirculation in endotoxic shock.
- To evaluate therapeutic strategies for managing macro- and microcirculatory abnormalities in experimental septic shock.
Main Methods:
- Male Wistar rats received endotoxin (LPS) or saline, followed by randomization to saline, norepinephrine, L-NMMA, or 1400W treatment.
- Hemodynamic parameters (blood pressure) and tissue oxygenation (ileum mucosal layer using EMPHO) were measured.
- Lactate levels and plasmatic nitrite/nitrate concentrations were analyzed.
Main Results:
- LPS-induced shock resulted in hypotension, acidosis, and increased nitrite/nitrate levels.
- Norepinephrine stabilized blood pressure but worsened lactate acidosis and microcirculatory oxygenation.
- Selective iNOS inhibition with 1400W improved blood pressure, reduced nitrite/nitrate, and preserved microcirculatory oxygenation without exacerbating acidosis.
Conclusions:
- Selective iNOS inhibitors, like 1400W, are superior to non-specific NOS inhibitors and norepinephrine in treating experimental septic shock.
- Targeting iNOS offers a promising therapeutic approach for improving both macro- and microcirculatory function in septic shock.
- Selective iNOS inhibition mitigates detrimental effects on microcirculation often seen with conventional vasopressor therapy.
