Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Abstract

Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

Figure 1

PDE inhibitors and cardiomyocyte contractile signaling crosstalk. PDEs modulate crosstalk and feedback signaling through cAMP, cGMP, and their associated kinases. PDE3, 4, and 5 are phosphorylated and activated by PKA while PDE5 is also phosphorylated by PKG. These PDEs in turn degrade cAMP or cGMP. Ultimately, this signaling cascade influences the activity of PKA and PKG which phosphorylate and modulate end effectors of myocyte contractility. Inhibition of PDE3, 4, and 5 isozymes in this system is thus expected to affect contractility. In particular, PDE3 or PDE4 inhibition may increase cAMP levels and result in enhanced contractility while contractile effects of PDE5 inhibitors may be dose dependent due to crosstalk effects mediated by PDE3. VGCC=Voltage-Gated Calcium Channel; PLB= Phospholamban; PLM=Phospholemman; RyR= Ryanodine Receptor; cTnI= Cardiac Troponin I; S-NO=S-Nitrosylation; L-Ca= L-type Calcium Channel.

Figure 2

Proposed mechanisms for PDE inhibitor-induced cytoprotection against myocardial ischemia-reperfusion injury. PDE5 inhibitors increase cGMP content, which activates PKG. PKG can subsequently activate mitoK_ATP channel and prevent the loss of ionic gradients in the necrotic pathway of ischemia/reperfusion injury. PDE5 inhibitors simultaneously initiate a signaling cascade involving PKC and ERK, leading to phosphorylation/induction of nitric oxide synthases (NOS) and release of nitric oxide (NO). This pathway also leads to opening of mitoK_ATP channel. Alternatively, PDE3, and PDE4 inhibitors may increase the activity of PKA leading to phosphorylation of eNOS and p38 MAPK. p38 MAPK activation may potentially result in translocation of 27 kDa heat shock protein (Hsp27) to the Z-disc, an event that may to stabilize the cytoskeleton and contractile fibers.