Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation.
OBJECTIVE
Adverse cardiac events in patients treated with the phosphodiesterase-5 inhibitor sildenafil for erectile dysfunction raised concerns about its safety in ischemic heart disease.


METHODS
In anesthetized open-chest rabbits, receiving 1.45 mg/kg sildenafil intravenously or saline 30 min prior to ischemia (n=12, each), infarct size (IS, triphenyltetrazolium), the area of no-reflow (ANR, thioflavin S) (% of the risk area, RA, blue dye), and regional myocardial blood flow (RMBF, radioactive microspheres) were measured after 30 min of coronary occlusion and 180 min of reperfusion. Left ventricular hemodynamics and dimensions (echocardiography) were determined in a separate series of animals (n=5, each).


RESULTS
Sildenafil significantly lowered arterial blood pressure before occlusion (-17 to -19 mmHg over 30 min), but during ischemia and reperfusion hemodynamics were comparable to controls. IS in treated animals (51+/-4%) did not significantly differ from control animals (47+/-4%). No major arrhythmias or lengthening of QT/QTc occurred. While sildenafil slightly increased RMBF and significantly reduced specific vascular resistance in the RA during reperfusion (51+/-7 versus 73+/-10 mmHg g min/ml, P<0.05), the ANR (46+/-3%) was similar to control animals (44+/-4%). Sildenafil reduced left ventricular dP/dt(max) (P<0.05) and dP/dt(min) (P<0.01) in non-ischemic conditions, and slightly during ischemia, along with a pronounced decrease in ischemic left ventricular end-diastolic pressure (9+/-2 versus 15+/-2 mmHg after saline, P<0.05), but did not attenuate acute ischemic left ventricular dilation.


CONCLUSIONS
Sildenafil reduced cardiac pre- and afterload, and parameters of left ventricular contractility. Myocardial necrosis and microvascular dysfunction were neither exacerbated nor attenuated.
Reffelmann
Thorsten
T
The Heart Institute, Good Samaritan Hospital, University of Southern California, 1225 Wilshire Boulevard, Los Angeles, CA 90017-2395, USA.
Kloner
Robert A
RA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004452:Echocardiography; D017379:Hypertrophy, Left Ventricular / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008833:Microcirculation; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D014655:Vascular Resistance / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate