Nitric oxide. To block or enhance its production during sepsis?
P. Wang, Z. F. Ba and I. H. Chaudry
Department of Surgery, Michigan State University, East Lansing.
BACKGROUND: Although it has been suggested that over-production of nitric
oxide (NO) is responsible for death during endotoxic shock or sepsis,
recent studies indicate that NO inhibition under such conditions is
detrimental. The reason for these seemingly controversial findings may be
because most studies were not standardized, ie, they were conducted at
different stages of sepsis. OBJECTIVE: To determine whether differential
alterations in endothelium-derived NO occur at different stages of sepsis.
DESIGN, INTERVENTION, AND MAIN OUTCOME MEASURES: Rats were subjected to
sepsis by cecal ligation and puncture (CLP) or sham operation, followed by
injection of 3 mL/100 g of body weight saline solution. At 2, 3.5, 10, or
20 hours after CLP, the thoracic aorta was isolated and responses to an
endothelium-dependent vasodilator, acetylcholine (via NO), and an
endothelium-independent vasodilator, nitroglycerine (directly providing NO)
were determined. RESULTS: Endothelium-dependent relaxation increased at 2
hours (ie, very early after the onset of sepsis), returned to sham levels
at 3.5 hours, but decreased at 10 and 20 hours after CLP (ie, later stage
of hyperdynamic sepsis and hypodynamic sepsis, respectively). Moreover, the
acetylcholine concentration, required to produce half-maximum relaxation,
decreased at 2 hours but increased at 20 hours after CLP. No significant
difference in nitroglycerine-induced relaxation was seen, however, in the
tested groups. The increased vascular relaxation at 2 hours after CLP was
not due to the upregulation of prostacyclin since cyclooxygenase inhibition
did not reverse this phenomenon. CONCLUSIONS: This study points out the
complexity of the alterations in NO production with the progression of
sepsis. The triphasic response of endothelium-derived NO should be taken
into account when attempting to manipulate NO levels during sepsis.
