Abstract 5541: Peroxynitrite Plays A Critical Role In Cardiovascular Collapse Following MRSA Sepsis
The gold standard therapy for sepsis is becoming less effective due to increasing microor-ganism resistance to antibiotics and cardiovascular collapse refractory to fluid resuscitation and vasopressors. Occurrence and severity of methicillin-resistant Staphylococcus aureus (MRSA) is increasing. In this study, we demonstrate a critical role of peroxynitrite formation in MRSA-induced cardiovascular collapse.
Method: Sheep were instrumented with Swan Ganz, femoral artery, and left atrium catheters to monitor hemodynamics for 24 h. Sepsis was induced by instillation of live MRSA (2.5X10^11CFU) into lungs by bronchoscope under anesthesia. Then, sheep were awakened, placed on ventilator, and fluid resuscitated. Urine output was measured via Foley catheter. Groups:
sham, no injury no treatment, n=6;
MRSA, received MRSA, n=4;
MRSA+VP, received MRSA and titrated with vasopressin when mean arterial pressure (MAP) fell by 10 mmHg, n=4;
MRSA+INO4885, received MRSA and treated with peroxynitrite decomposition catalyst started 6 h post-injury (0.1 mg/kg bolus followed by 0.02 mg/kg/h), n=4; and
MRSA+VP+INO4885, received MRSA, treated with vasopressin and INO4885, n=4.
Results: ~60 % of animals received MRSA showed a positive blood culture. MRSA induced severe hypotension refractory to aggressive fluid and vasopressin. INO4885 largely prevented the severe hypotension. Combined with vasopressin, INO4885 more effectively reversed the hypotension (Table 1⇓). Inhibition of peroxynitrite formation also markedly reduced a severe vascular leak by MRSA.
Conclusion: Peroxynitrite inhibition may be a novel treatment option against MRSA sepsis-induced cardiovascular collapse refractory to vasopressors. These findings are especially provocative since peroxynitrite is the product of excessive nitric oxide regardless of which NOS isoform is involved, and there remains a major debate whether the use of NOS inhibitors in management of sepsis is beneficial.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).