Cardiac Uses of Phosphodiesterase-5 Inhibitors

Bryan G. Schwartz, MD; Laurence A. Levine, MD; Gary Comstock, MD; Vera J. Stecher, PhD; Robert A. Kloner, MD, PhD

Disclosures

J Am Coll Cardiol. 2012;59(1):9-15. 

In This Article

Cardioprotection

Mechanisms similar to those involved in preventing doxorubicin cardiotoxicity also seem to protect the heart from acute infarction, as reviewed elsewhere.[18] Briefly, NO synthesis by endothelial- and especially inducible-NO synthase is an essential component of cardioprotection.[19,20] Numerous stimuli, including PDE5Is, initiate the NO synthase signaling cascade by first activating protein kinase C or extracellular-signal-regulated kinase, which mediates survival pathways in many cell types—including the delayed cardioprotective effect of sildenafil.[18] Nitric oxide directly mediates early cardioprotection[21–24] and also triggers delayed cardioprotection by increasing cGMP levels and protein kinase G activity.[25–27] Mitochondrial adenosine triphosphate (ATP)-dependent potassium channels are a critical downstream target of cardioprotection pathways. Mitochondrial integrity is essential to cell survival, by maintaining ATP synthesis and calcium homeostasis. Nitric oxide acts directly and indirectly through protein kinase G to open mitochondrial ATP potassium channels, which protect myocytes by compensating for the altered membrane potential and enabling protons to be pumped out of the mitochondria, which maintains the electrochemical gradient necessary for ATP synthesis and calcium transport.[18] Additionally, PDE5Is also seem to promote cardioprotection through NO-dependent up-regulation of Bcl-2, which promotes cell survival by inhibiting the mitochondrial permeability transition pore.[18]

Numerous studies have reported a reduction in infarct size in animals treated with sildenafil compared with placebo.[19–22,25,26] Sildenafil provided cardioprotection when administered immediately,[25] 30 min,[21] 24 h,[21,22] or chronically for 4 weeks[19] before a coronary occlusion or during coronary reperfusion.[26] Likewise, tadalafil[27,28] and vardenafil[24] reduced infarct size when given 30 to 120 min before coronary occlusion. The duration of cardioprotection from tadalafil remained until 36 to 40 h after a single dose, and repeat administration at 36 and 72 h extended protection until 108 h.[23] In addition to reducing infarct size, administration of PDE5Is before coronary occlusion in animal models increased endothelial- and inducible-NO synthase,[19,20] reduced cardiac hypertrophy,[19] reduced apoptosis,[19] preserved fractional shortening,[27] and improved survival.[19,27] In a dog model mimicking cardiopulmonary bypass, vardenafil improved recovery of the ventricular end-systolic pressure volume relationship, increased coronary blood flow, and preserved endothelial function.[29] At least 1 study reported that sildenafil had no effect on infarct size but did improve coronary vascular resistance and certain hemodynamic parameters during experimental myocardial infarction.[30]

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