Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model.
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)) K(ATP) channel blocker. Hearts were then subjected to 20 min global, or 35 min regional ischaemia at 37( composite function)C 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 K(ATP) channel.
du Toit
Eugene Francois
EF
Department of Medical Physiology, Faculty of Health Science, University of Stellenbosch, Tygerberg, South Africa. efdt@sun.ac.za
Rossouw
Ellen
E
Salie
Ruduwaan
R
Opie
Lionel Henry
LH
Lochner
Amanda
A
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones
D009712:Nucleotides, Cyclic; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases