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Sildenafil Citrate in a Donation After Circulatory Death Experimental Model of Renal Ischemia-Reperfusion Injury

Hosgood, Sarah A.1,3; Randle, Lucy V.2; Patel, Meeta1; Watson, Christopher J.2; Bradley, John A.2; Nicholson, Michael L.1

doi: 10.1097/TP.0000000000000283
Basic and Experimental Research

Introduction 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.

Conclusion Sildenafil had a vasodilatory action and increased levels of cGMP but did not affect recovery of renal function or protect against I/R injury.

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.

The authors declare no funding or conflicts of interest.

E-mail: sah76@le.ac.uk

S.A.H. designed the study, performed the experiments, analyzed the data, and wrote the article. L.R. performed the experiments, analyzed the data, and reviewed the article. M.P. performed the experiments, analyzed the data, and reviewed the article. C.J.W. designed the study and reviewed the article. J.A.B. designed the study and reviewed the article. M.L.N. designed the study and reviewed the article.

Received 13 March 2014. Revision requested 31 March 2014.

Accepted 2 May 2014.

© 2014 by Lippincott Williams & Wilkins