High Flow Attenuates Reactivity of Porcine Pulmonary Arteries to Phenylephrine and U‐46619

Abstract

A model has been developed in vivo to study the effects of high blood flow on the pulmonary vasculature. Briefly, the branch of the pulmonary artery (PA) of 3-4 week old piglets, which supplies the left lower lobe of the lung is anastamosed end-to-side to the aorta to substantially increases the flow (3 fold) to this lobe. Branches of the PA (1-2 mm diameter) harvested from this lobe can be compared to vessels in the contralateral lobe to determine the effects of flow on signaling pathways. Constriction in response to the thromboxane mimetic, U-46619 (10−7 M, n=8) and phenylephrine (10−5 M, n=8) is blunted (p<.05 for both agonists) in vessels exposed to high flow for 72 hours. Application of the eNOS inhibitor L-NMMA (10−3 M) or two different rho-kinase inhibitors (Y-27632, 10−4 M or HA-1077, 10−5 M) altered contractility but did not significantly alter the difference in reactivity between shunted vessels versus controls. Preliminary results suggest that a combination of inhibitors of arachidonic acid metabolism that block cyclooxygenases (indomethacin, 100 μM), cytochrome P450 enzymes (DDMS, 10 μM) and lipoxygenases (NDGA, 20 μM) eliminate the difference in contractility produced by U46619. Our results demonstrate that high flow reduces reactivity in pulmonary arteries within 48-72 hours, which does not appear to be due to changes in the eNOS or Rho kinase signaling pathways. However, the decrease in contractility induced by high flow may be due to changes in arachidonic acid metabolism. This work is supported by NHLBI 68627, 49294 and 69996.