DIFFERENTIAL INFLUENCE OF ARACHIDONIC VS EICOSAPENTAENOIC ACID ON EXPERIMENTAL PULMONARY-HYPERTENSION

The impact of the 2- and 3-series prostanoid precursors arachidonic ac id (AA) and eicosapentaenoic acid (EPA) on experimental pulmonary hype rtension was investigated. The model of buffer-perfused rabbit lungs w as stimulated by infusion of Escherichia coli hemolysin (HlyA), which is known to provoke sustained thromboxane (Tx)-mediated pulmonary hype rtension. Release of di- and trienoic Tx into the recirculating perfus ate was quantified by a post-high-performance liquid chromatography en zyme-linked immunosorbent assay technique. HlyA at 0.08 hemolytic unit /ml caused a sustained rise in pulmonary arterial pressure (PAP; maxim um increase 14 +/- 2 mmHg) accompanied by progressive TxB(2) liberatio n (maximum perfusate concn 33 +/- 4 pg/ml, baseline <2 pg/ml). Between 5 and 30 nM, AA provoked a transient monophasic rise in PAP (maximum presser response 1.5-15 mmHg) and concomitant TxB(2) release (peak con cn 2-30 pg/ml). Simultaneous administration of HlyA and AA exhibited a dditive effects with regard to mediator release and presser responses. EPA at 200-2,000 nM caused a transient rise in PAP similar to that pr ovoked by 5-30 nM AA (maximum presser response 3-18 mmHg). This was ac companied by liberation of TxB(2) (peak concn 16 +/- 5 and 28 +/- 4 pg /ml after 1,000 and 2,000 nM EPA) and TxB(3) (peak concn 9 +/- 4 and 3 0 +/- 3 pg/ml). Combined application of HlyA and EPA resulted in appro ximate addition of the TxB(2) release reaction to each single compound , and TxB(3) liberation more than doubled (maximum concn 59 +/- 12 pg/ ml). The presser responses to HlyA-EPA (200-2,000 nM) did not, however , surpass those to HlyA-AA (5-30 nM). We conclude that the potency of the alternate Lipid mediator precursor EPA to provoke Tx-mediated pulm onary hypertension is nearly two orders of magnitude below that of AA under baseline conditions and in a model of pulmonary hypertension.