The effects of selectively inhibiting synthesis of
thromboxane A2 (TXA2) with
dazoxiben and of all
cyclooxygenase products with
indomethacin were studied in goats after infusion of 5 X 10(8) live Escherichia coli bacteria/kg. Pulmonary and systemic pressures, cardiac output, and double
indicator dilution extravascular lung water (EVLW) were measured at 15-min intervals. EVLW was determined gravimetrically at 6 hr to confirm the final double
indicator dilution values. Plasma levels of TXA2 and
prostacyclin (PGI2) were measured as their stable metabolites, TXB2 and
6-keto-PGF1 alpha, respectively.
Dazoxiben blocked the increase in plasma TXB2, prevented
pulmonary hypertension, and attenuated the increase in EVLW after E. coli. Mean gravimetric EVLW was 8.7 ml/kg in the
dazoxiben-treated group compared to 11.3 ml/kg in the untreated control group.
Indomethacin blocked the increased plasma TXB2 and
6-keto-PGF1 alpha, attenuated
pulmonary hypertension, and prevented almost all increases in EVLW. Mean gravimetric EVLW was 8.2 ml/kg after
indomethacin. We conclude that in acute
bacteremia, the early
pulmonary hypertension is mediated largely by TXA2 (however, a second phase of
hypertension results from non-
cyclooxygenase products), either production of
cyclooxygenase products (perhaps PGI2) inhibits part of the action of pulmonary
vasoconstrictors, or
indomethacin stimulates the production of other
vasoconstrictors (such as
lipoxygenase products), and
indomethacin prevents the accumulation of EVLW by blocking formation of
cyclooxygenase products or by other nonspecific actions.