Mechanisms underlying increased reactivity of pulmonary arteries contralateral to a localized high-flow anastomosis Sandra Pfister, PhD, Lewis Somberg,

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Mechanisms underlying increased reactivity of pulmonary arteries contralateral to a localized high-flow anastomosis Sandra Pfister, PhD, Lewis Somberg, MD, Timothy Lowry, PhD, Ying Gao, MS, Meetha Medhora, PhD, Elizabeth R. Jacobs, MD, MBA The Journal of Thoracic and Cardiovascular Surgery Volume 141, Issue 2, Pages 425-431 (February 2011) DOI: 10.1016/j.jtcvs.2010.07.007 Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 The inset schematic denotes the sources and effects of NO on pulmonary vascular tone and site of action of l-NMMA. Rings from high-flow pigs (A) or low-flow pigs (B) were treated with l-NMMA (10−3 mol/L) or vehicle, allowed to equilibrate for 30 minutes, and then a concentration response to U46619 was obtained. See legends for identification of treatment groups. Single asterisks denote concentration curves of left and right pulmonary arteries that are different one from the other based on 2-way repeated measures analysis of variance (P < .05). Double asterisks indicate differences in response curves of pulmonary arteries treated with l-NMMA relative to that of pulmonary arteries treated with vehicle. l-NMMA increased basal tension and shifted the concentration response to U46619 of all pulmonary arteries up and to the left, regardless of the flow state of the shunt. PA, Pulmonary artery; l-NMMA, l-Ng-monomethylarginine; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase. The Journal of Thoracic and Cardiovascular Surgery 2011 141, 425-431DOI: (10.1016/j.jtcvs.2010.07.007) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Western blots for detection of eNOS immunospecific protein in homogenized pulmonary artery vessels from left or right lower lobe of 7 high-flow pigs and 4 low-flow pigs were performed. Representative examples of images from these studies appear in part A. Ponceau red (below the eNOS Westerns) was used to correct for loading of protein. Ratios of densities of L/R eNOS bands from the same Western blots appear in part B. There were no differences in eNOS protein expression in left and right lower lobe pulmonary arteries in samples obtained from either high- or low-flow pigs. eNOS, Endothelial nitric oxide synthase; L/R, left/right. The Journal of Thoracic and Cardiovascular Surgery 2011 141, 425-431DOI: (10.1016/j.jtcvs.2010.07.007) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 A, This schematic depicts 3 major pathways of arachidonic acid metabolism, the dominant vasoactive effects of metabolites of this pathway, and the site of action of inhibitors we used in these experiments. The blue box shows products that are (1) blocked by NDGA and CDC, (2) reported to increase the tone of pulmonary arteries, and (3) synthesized in increased amounts by right pulmonary arteries contralateral to systemic pulmonary shunts (see Figure 5). B, U46619 concentration response curves of pulmonary arteries from high-flow pigs treated with vehicle or an inhibitor cocktail that included indomethacin (100 μmol/L), DDMS (20 μmol/L), and NDGA (20 μmol/L) for 30 minutes were obtained. The concentration response curves of left and right lower lobe pulmonary arteries after treatment with the cocktail of inhibitors were not different (n = 6; P > .5, 2-way repeated measures analysis of variance). C, Treatment with indomethacin (100 μmol/L) or DDMS (20 μmol/L; inset) did not eliminate the differences in contractility of right and left lower lobe pulmonary arteries to U46619 (n = 5; P < .05 by 2-way repeated measures analysis of variance). D, Treatment with NDGA (20 μmol/L) or CDC (10 μmol/L; inset) eliminated the differences between reactivity of left and right lower lobe pulmonary arteries to U46619 (n = 6 each). Contraction of left lower lobe pulmonary arteries was unaffected by NDGA treatment relative to controls, whereas reactivity of the right lower lobe pulmonary arteries was significantly decreased by this inhibitor (n = 6; P < .05 by analysis of variance). AA, Arachidonic acid; PA, pulmonary artery; DDMS, dibromo-dodecynyl-methylsulfimide; NDGA, nordihydroguaiaretic acid; CDC, cyanocinnamate; CYP, cytochrome P450; HETE, 12-hydroxyeicosatrienoic acid; EET, epoxyeicosatrienoic acids; PG, prostaglandin; TxA2, thromboxane A2; NDGA, nordihydroguaiaretic acid. The Journal of Thoracic and Cardiovascular Surgery 2011 141, 425-431DOI: (10.1016/j.jtcvs.2010.07.007) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Western blots for 15-LOX2 were performed on homogenates of microdissected pulmonary arteries from left and right lower lobe pulmonary arteries, and densities of immunospecific bands for these proteins and beta actin were compared (n = 6 samples from left and right lower lobe pulmonary arteries each). The ratio of actin-normalized 15-LOX2 protein density was higher in left than right pulmonary artery homogenates by a factor of roughly 2 (P < .05; n = 6). LOX, Lipoxygenase; IDV, independent diversity values. ∗P < .05 left relative to right. The Journal of Thoracic and Cardiovascular Surgery 2011 141, 425-431DOI: (10.1016/j.jtcvs.2010.07.007) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Arachidonic acid metabolism in isolated pulmonary artery segments. A representative chromatogram from a pair of shunted and unshunted pulmonary arteries of high-flow pigs (see legend for identification code) is shown. Migration times of known standards are indicated. Results were normalized to vessel weight and expressed as cpm/mg. A peak that elutes at 20 to 21 minutes (fractions 100–105) coincident with authentic 12-HETE is higher in the right pulmonary artery sample. AA, Arachidonic acid; HETA, hydroxyeicosatrienoic acid; RPA, right pulmonary artery; LPA, left pulmonary artery. The Journal of Thoracic and Cardiovascular Surgery 2011 141, 425-431DOI: (10.1016/j.jtcvs.2010.07.007) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions