Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model

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Title Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model
Author Du Toit, Eugene; Rossouw, Ellen; Salie, Ruduwaan; Opie, Lionel Henry; Lochner, Amanda
Journal Name Cardiovascular Drugs and Therapy
Year Published 2005
Place of publication London England
Publisher Nature Publishing Group
Abstract We have previously shown that NO-donor induced elevation in myocardial cGMP levels is associated with improved reperfusion function of the isolated rat heart. The phosphodiesterase 5 (PDE 5) inhibitor, sildenafil could potentially increase myocardial cGMP levels and thus protect the heart against ischaemic/reperfusion injury. Methods: To test our hypothesis we treated the isolated working rat heart with vehicle, OR sildenafil (10, 20, 50, 100, 200 nM), OR sildenafil (50 nM) plus a sarcolemmal (HMR 1098) or a mitochondrial (5-Hydroxydecanoate (5-HD)) KATP channel blocker. Hearts were then subjected to 20 min global, or 35 min regional ischaemia at 37C before reperfusion function (aortic output, coronary flow and aortic pressure) and infarct size were documented. Pre-ischaemic, ischaemic and reperfusion myocardial cAMP and cGMP concentrations were determined. Results: Low concentrations of sildenafil (10, 20 and 50 nM) improved reperfusion aortic output (AO) recovery (61.4± 4.5%, 64.8 ± 5.2% and 62.3 ± 5.0% vs. 45.4 ± 3.8% for controls (p < 0.05)) and infarct size, while high concentrations (200 nM) worsened AO recovery (24.9 ± 4.9.0%, p < 0.05). Myocardial cGMP levels of ischaemic tissue were elevated (34.7 ± 2.4 vs. 27.3 ± 2.2 pmol/g ww) and cAMP levels were suppressed (0.59 ± 0.03 vs. 0.87 ± 0.06 nmol/g ww) in the sildenafil (50 nM) treated hearts. Co-perfusion with sildenafil plus HMR 1098 decreased AO recovery (21.7 ± 7.6% vs. 62.3 ± 5.0% for sildenafil alone, p < 0.05) and increased infarct size (29.7 ± 2.04% vs. 8.6 ± 2.39% for sildenafil alone, p < 0.05).Similarly, sildenafil plus 5-HD decreased reperfusion AO recovery (44.4 ± 6.0% vs. 62.3 ± 5.0% for sildenafil alone, p < 0.05) and increased infarct size (33.8 ± 1.62% vs. 8.6 ± 2.39% for sildenafil alone, p < 0.05). Conclusions: (1) Pretreatment with low concentrations of sildenafil (20–50 nM) improves, while higher concentrations (200 nM) worsen reperfusion function in this model. (2) Low concentrations of sildenafil (20–50 nM) decrease infarct size while the higher concentrations had no effect. (3) These protective properties of low concentrations of sildenafil may be related to its cGMP elevating and cAMP suppressing effects in the ischaemic heart. (4) Possible end-effectors for sildenafil in the ischaemic heart include the mitochondrial and sarcolemmal KATP channel.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1007/s10557-005-6894-2
Volume 19
Page from 23
Page to 31
ISSN 0007-1188
Date Accessioned 2009-06-29
Date Available 2009-09-14T07:15:40Z
Language en_AU
Research Centre Griffith Health Institute
Faculty Griffith Health Faculty
Subject Cardiology (incl Cardiovascular Diseases)
URI http://hdl.handle.net/10072/25666
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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