title: Sildenafil citrate in a donation after circulatory death experimental model of renal ischemia-reperfusion injury.
abstract: BACKGROUND
  Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic guanosine 3',5'-monophosphate (cGMP) and therefore may be useful in reducing the detrimental effects of ischemia-reperfusion (I/R) injury. The aim of this study was to assess the effects of the phosphodiesterase-5 inhibitor sildenafil, on I/R injury in a porcine model of donation after circulatory death kidney transplantation.
  
  
  METHODS
  Kidneys were subjected to 20 min warm ischemia followed by 2 or 18 hr of cold storage (n=6 kidneys per group). After preservation kidneys were reperfused on an ex vivo perfusion system for 3 hr with an oxygenated blood based solution. Kidneys were treated with 1.4 mg/kg sildenafil infused 10 min before and for 20 min after reperfusion (n=6 kidneys per group). Renal function and injury markers were measured throughout reperfusion.
  
  
  RESULTS
  Prolonged cold ischemia (CI) significantly reduced levels of cGMP (2 hr 3.5 [1.5-5.7] vs. 18 hr 1.2 [0.3-2.8] pmol/mL; P=0.010). The administration of sildenafil significantly increased the levels (P=0.047, 0.064). Sildenafil improved the renal blood flow for the first 30 min in the 2-hr group (sildenafil, 81.8 [43.8-101.9] vs. control 40.2 [6.4-76.9] mL/min/100 g; P=0.026) and up to 60 min in the 18-hr group (sildenafil, 67.4 [38.0-87.0] vs. control 36.2 [30.5-50.0] mL/min/100 g; P=0.009) during reperfusion. Renal function was significantly impaired after 18-hr CI (P=0.0.26), and treatment with sildenafil did not improve renal function in the 2-hr (P=0.384) or 18-hr CI (P=0.099) groups.
  
  
  CONCLUSIONS
  Sildenafil had a vasodilatory action and increased levels of cGMP but did not affect recovery of renal function or protect against I/R injury.
authors.affiliation: 1 Department of Infection, Immunity and Inflammation, Transplant Group, The University of Leicester, Leicester General Hospital, Leicester, United Kingdom. 2 Department of Surgery, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom. 3 Address correspondence to: Sarah A Hosgood, M.D., Department of Infection, Immunity and Inflammation, Transplant Group, The University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Hosgood
authors.forename: Lucy V
authors.initials: LV
authors.lastname: Randle
authors.forename: Meeta
authors.initials: M
authors.lastname: Patel
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Watson
authors.forename: John A
authors.initials: JA
authors.lastname: Bradley
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D019540:Area Under Curve; D050377:Cold Ischemia; D003401:Creatine / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood; D007668:Kidney / Q000187:drug effects*; D016030:Kidney Transplantation / Q000379:methods*; D009569:Nitric Oxide / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects; D010879:Piperazines / Q000009:adverse effects*; D011687:Purines / Q000009:adverse effects; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects*; D013552:Swine; D013997:Time Factors; D052096:Warm Ischemia
chemical_list: D019332:Endothelin-1; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; D003401:Creatine