Sildenafil citrate augments myocardial protection in heart transplantation.
BACKGROUND
Sildenafil citrate has been shown to induce myocardial protective effects in a variety of experimental settings. Whether these effects could be used to enhance myocardial protection afforded by crystalloid cardioplegia, volatile anesthesia and hypothermia during cardiac transplantation remains to be established.


METHODS
We investigated the use of sildenafil-mediated cardioprotection in a rat model of heterotopic cardiac transplantation. Sildenafil citrate (0.7 mg/kg) was administered intravenously to the donor 30 min before onset of ischemia or 5 min before reperfusion in the recipient. In situ cardioplegic arrest was followed by an ischemic time of 3 or 6 hr, transplantation, and blood reperfusion. Myocardial functional recovery was studied in vivo by using a left ventricular balloon and cellular injury quantified by assay of troponin I release and apoptosis.


RESULTS
Sildenafil preconditioning but not postconditioning significantly improved initial myocardial systolic and diastolic function after 3 hr of hypothermic cardioplegic arrest (114+/-4 mm Hg vs. 83+/-4 mm Hg generated pressure, [P<0.01]). The protective effect of sildenafil declined over a 3-hr period of reperfusion along with overall myocardial function, no longer reaching statistical significance at 3 hr. The protective effects of sildenafil were abolished by the putative blocker of the mitochondrial ATP sensitive potassium channel, 5-hydroxydecanoate, before sildenafil administration. Protein kinase C delta showed significant translocation after sildenafil administration in the donor.


CONCLUSIONS
We conclude that sildenafil citrate pretreatment augments myocardial functional recovery after an ischemic time relevant to clinical cardiac transplantation. This effect is associated with protein kinase C activation/translocation and inhibited by 5-hydroxydecanoate.
Botha
Phil
P
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. P.Botha@ncl.ac.uk
MacGowan
Guy A
GA
Dark
John H
JH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003652:Decanoic Acids / Q000627:therapeutic use; D003971:Diastole / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D016027:Heart Transplantation / Q000379:methods / Q000502:physiology*; D006880:Hydroxy Acids / Q000627:therapeutic use; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D023421:Models, Animal; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D013599:Systole / Q000187:drug effects; D016042:Transplantation, Heterotopic; D019210:Troponin I / Q000097:blood; D014665:Vasodilator Agents / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D019210:Troponin I; D014665:Vasodilator Agents; C052853:5-hydroxydecanoic acid; D000068677:Sildenafil Citrate