EFFECT OF NITRIC-OXIDE SYNTHASE INHIBITION DURING GROUP-B STREPTOCOCCAL SEPSIS IN NEONATAL PIGLETS

Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Argini ne analogs, such as N-omega-nitro-L-arginine methyl ester (L-NAME), ar e competitive antagonists of NO synthase and inhibit NO synthesis. Gro up B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lun g vascular injury, and reduced cardiac output in both human newborns a nd neonatal piglets. Lung vascular injury associated with prolonged GB S infusion in piglets may attenuate NO production and thus promote sev ere pulmonary hypertension. We studied the effect of the NOS inhibitor , L-NAME and the precursor of NO, L-arginine, on pulmonary and systemi c hemodynamics during late-phase GBS sepsis in the piglet model. Neona tal piglets were anesthetized, ventilated with room air, and randomize d to receive a continuous infusion of saline (n = 5) or GBS (n = 5) fo r 4 h. After 3 h of infusion, both groups received a bolus of L-NAME ( 3 mg/kg). Hemodynamic and gas exchange indices were measured at baseli ne, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treat ment. L-NAME treatment caused 1) significant increases in mean pulmona ry arterial pressure, pulmonary vascular resistance, mean systemic art erial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for t he two groups; 3) greater reduction in cardiac output and SV in the GB S compared with the control group; and 4) no significant alterations i n arterial partial pressure of oxygen or the difference between alveol ar and arterial partial pressure of oxygen for either group. L-Arginin e (1 g/kg) infusion after 3 h of GBS infusion (n = 3) caused no signif icant charges in any measured hemodynamic or gas-exchange variable. We conclude that 1) endogenous NO synthesis is ongoing during late-phase GBS-induced pulmonary hypertension in neonatal piglets, and 2) NO syn thesis is not limited by the substrate L-arginine in this model. NO sy nthase inhibitors alone appear to be contraindicated in the treatment of neonatal GBS sepsis due to worsening pulmonary hypertension and pro gressive decline in cardiac output.