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Rejected donor lungs may be successfully transplanted after being reconditioned ex vivo.

Objective-ADP plays an important role in platelet aggregation by activating P2Y 12 receptors. We assessed the hypothesis that P2Y 12 receptors are expressed in vascular smooth muscle cells (VSMC). Methods and Results-P2Y 12 receptor mRNA was found to have a high expression among the P2 receptors in human VSMC, significantly higher than the other 2 ADP receptors (P2Y 1 and P2Y 13 , real-time polymerase chain reaction). Western blots gave a band of 50 kD, similar to that in platelets. To unmask a P2Y 12 receptor-mediated vasoconstriction by simulating the in vivo situation, vessels were precontracted to a submaximal level. 2-MeSADP stimulated contractions in vessel segments from internal mammary artery (IM), IM branches and small veins (E max ϭ15Ϯ6% of 60mmol/L K ϩ contraction, pEC 50 ϭ5.6Ϯ0.6, E max ϭ21Ϯ1%, pEC 50 ϭ6.8Ϯ0.1, and E max ϭ48Ϯ9%, pEC 50 ϭ6.6Ϯ0.4). The selective P2Y 12 antagonist AR-C67085 blocked 2-MeSADP contractions. The contraction was not reduced in patients using clopidogrel, a drug inhibiting ADP-induced platelet aggregation by blocking the P2Y 12 receptor. This may be explained by the high instability of the active clopidogrel metabolite that never reaches the systemic circulation. Conclusion-ADP acting on P2Y 12 receptors not only is important for platelet activation but also stimulates vasoconstriction. Stable drugs with antagonistic effects on P2Y 12 receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm. Key Words: vasoconstriction Ⅲ P2Y receptors Ⅲ platelets Ⅲ ADP E xtracellular nucleotides such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate, and uridine diphosphate are released from sympathetic nerves, platelets, and endothelial and inflammatory cells. 1 Nucleotides induce vasoconstriction-stimulating P2 receptors on vascular smooth muscle cells (VSMC), regulating vascular tone and blood pressure. 1,2 Furthermore, extracellular nucleotides have been shown to mediate growth stimulation and migration in VSMC. 3,4 P2 receptors can be divided into 2 classes on the basis of their signal transmission mechanisms and their characteristic molecular structures: ligand-gated intrinsic ion channels, P2X receptors, and G-protein-coupled P2Y receptors. The P2Y family is composed of 8 cloned and functionally defined subtypes. [5][6][7][8][9] ADP is stored in high concentrations in platelet granula and is released as a positive feedback mechanism in response to most platelet activators. After release, ADP augments platelet aggregation by stimulation of P2Y 12 and P2Y 1 receptors. 10 The first clinical application of P2 receptor antagonists has been the use of thienopyridines as platelet aggregation inhibitors. Clopidogrel and ticlopidine are prodrugs that are converted in the liver into irreversible antagonists against P2Y 12 receptors. Clopidogrel is more efficient than aspirin in reducing the composite end point myocardial infarction, stroke, and death in patients with vascular disease...

1 The present study was aimed at examining P2 receptor-mediated vasodilatation in human vessels. The isometric tension was recorded in isolated segments of the human left internal mammary artery branches precontracted with 1 mM noradrenaline. 2 Endothelial denudation abolished the dilator responses. 3 The selective P2Y 1 agonist, 2-MeSADP, induced a potent vasodilatation (pEC 50 ¼ 6.970.1). The P2Y 1 antagonist of 10 mM, MRS 2216, shifted the 2-MeSADP concentration-response curve 1.1 log units to the right. The combined P2Y 1 and P2X agonist, 2-MeSATP, stimulated a dilatation with a potency similar to that of 2-MeSADP. Furthermore, MRS 2216 had a similar antagonistic effect on both 2-MeSATP and 2-MeSADP indicating that P2X receptors do not mediate vasodilatation. 4 Both the P2Y 2/4 agonist, UTPgS and the P2Y 6 agonist, UDPbS, stimulated potent dilatations (pEC 50 ¼ 7.870.4 for UTPgS and 8.470.2 for UDPbS). 5 The 2-MeSADP-induced nitric oxide (NO)-mediated dilatation was studied in the presence of 10 mM indomethacin, 50 nM charybdotoxin and 1 mM apamin. The involvement of the endotheliumderived hyperpolarising factor (EDHF) was investigated in the presence of 0.1 mM L-NOARG and indomethacin. The involvement of prostaglandins was investigated in the presence of L-NOARG, charybdotoxin and apamin. Both NO, EDHF and prostaglandins mediated 2-MeSADP dilatation with similar efficacy (E max ¼ 2575% for NO, 2576% for EDHF and 2775% for prostaglandins). 6 In conclusion, extracellular nucleotides induce endothelium-derived vasodilatation in human vessels by stimulating P2Y 1 , P2Y 2/4 and P2Y 6 receptors, while P2X receptors are not involved. Endothelial P2Y receptors mediate dilatation by release of EDHF, NO and prostaglandins. British Journal of Pharmacology (2003) 138, 1451-1458. doi:10.1038/sj.bjp.0705186 Keywords: coronary circulation; endothelium; endothelium-derived hyperpolarising factor; human; nitric oxide; nucleotide; P2 receptor; vasodilatationAbbreviations: 2-MeSADP, 2-methylthio adenosine 5 0 -diphosphate; 2-MeSATP, 2-methylthio adenosine 5 0 -triphosphate; abMeATP, ab-methylene adenosine 5 0 -triphosphate; Ach, acetylcholine; ADP, adenosine diphosphate; ANOVA, the one-way analysis of variance; ATP, adenosine triphosphate; EC, endothelial cells; EC 50 , effective concentration (e.g. 50% of maximum); EDHF, endothelium-derived hyperpolarising factor; LIMA, left internal mammary artery; L-NOARG, N$-nitro-L-arginine; mRNA, messenger ribonucleic acid; MRS 2179, 2 0 -deoxy-N6-methyladenosine-3 0 ,5 0 -bisphosphate; MRS 2216, 2-chloro-2 0 -deoxy-6-methyladenosine-3 0 ,5 0 -bisphosphate; NA, noradrenaline; NO, nitric oxide; t-PA, tissue-plasminogen activator; UDP, uridine diphosphate; UDPbS, uridine 5 0 -O-2-thiodiphosphate; UTP, uridine triphosphate; UTPgS, uridine 5 0 -O-3-thiotriphosphate; VSMC, vascular smooth muscle cells

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This study indicates that clearance estimations based on cystatin C are more accurate compared with estimations based on creatinine in determining GFR in cardiac surgery. Cystatin C has, in this study population, a stronger correlation to iohexol clearance than creatinine.

A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that had been deemed unsuitable for transplantation by the Scandiatransplant, Eurotransplant, and UK Transplant organizations because the arterial oxygen pressure was less than 40 kPa. The three-month survival of patients undergoing transplant with these lungs was 100%. One patient died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are still alive and well 24 months after transplantation, with no signs of bronchiolitis obliterans syndrome. The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation circuit using STEEN solution mixed with erythrocytes, to dehydrate edematous lung tissue. Functional evaluation was performed with deoxygenated perfusate at different inspired fractions of oxygen. The arterial oxygen pressure was significantly improved in this model. This ex vivo evaluation model is thus a valuable addition to the armamentarium in increasing the number of acceptable lungs in a donor population with inferior arterial oxygen pressure values, thereby, increasing the lung donor pool for transplantation. In the following paper we present our clinical experience from the first six patients in the world. We also present the technique we used in detail with flowchart.

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