Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury

Abstract

Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after myocardial infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), the phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO1TAD) in C57Bl6J mice subjected to 6-minute left anterior descending artery ligation followed by reperfusion. We measured plasma and cardiac concentrations of cGMP during early reperfusion, quantified myocardial necrosis and inflammation by serial troponin-I (TnI) and myeloperoxidase-positive cell infiltration at day 3, and evaluated LV function and remodeling after 4 weeks using echocardiography and pressure-conductance catheterization. Administration of iNO, TAD, or both during I/R was safe and hemodynamically well tolerated. Compared with untreated mice (CON), only iNO1TAD increased plasma and cardiac-cGMP levels during early reperfusion (80 6 12 versus 36 6 6 pmol/ml and 0.15 6 0.02 versus 0.05 6 0.01 pmol/mg protein, P , 0.05 for both). Moreover, iNO1TAD reduced TnI at 4 hours to a greater extent (P , 0.001 versus CON) than either alone (P , 0.05 versus CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared with CON, iNO1TAD was associated with increased fractional shortening (43 6 1 versus 33 6 2%, P , 0.01), larger stroke volumes (14.9 6 1.2 versus 10.2 6 0.9 ml, P , 0.05), enhanced septal and posterior wall thickening (P , 0.05 and P , 0.001, respectively), and attenuated LV dilatation (P , 0.001), whereas iNO or TAD alone conferred less benefit. Thus, iNO1TAD has superior efficacy to limit early reperfusion injury and attenuate adverse LV remodeling. Combination of inhaled NO with a long-acting PDE5 inhibitor may represent a promising strategy to reduce ischemic damage following reperfusion and better preserve LV function.

Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair

“…Therefore, such combined therapies may represent promising strategies for translational research to improve the outcome of I/R‐injury in patients (Lux et al. ).…”

“…The associated increase in cGMP-signaling after the combined treatment suggests the importance of this pathway for beneficial long term structural and functional myocardium remodeling. Therefore, such combined therapies may represent promising strategies for translational research to improve the outcome of I/R-injury in patients (Lux et al 2016).…”

Protective effect of tadalafil in diabetic nephropathy induced rat model

“…16 In addition, the acute effect of tadalafil as a reno protective agent was demonstrated in experimental renal ischemia/reperfusion injury model in the rat. 17 More recently, Wang et al demonstrated that tadalafil is effective and safe for the treatment of diabetic neuropathy as it increases regional blood flow in the sciatic nerve tissue and improves peripheral nerve function in type II diabetic mice. 18 In the present study, chronic low dose tadalafil treatment attenuated the progression of DN in STZ-induced diabetic rats.…”

cGMP at the centre of attention: emerging strategies for activating the cardioprotective PKG pathway

“…In this brief review, we will focus on pharmacological aspects of the cGMP–PKG pathway with updates from recent preclinical and clinical studies in relation to its direct effect on the heart. We also refer readers to excellent recent reviews providing in-depth overview of NO–cGMP–PKG pathway such as [ 40 ].…”