Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG

Abstract

Background and purpose: The type-5 PDE inhibitor vardenafil reduces myocardial infarct size in situ, following ischemia/ reperfusion, when applied at reperfusion in animal models. Little is known about the underlying protective signaling. Here, we test whether vardenafil is protective in rat isolated hearts and in a cell model of calcium stress. Experimental approach: Infarct size in rat isolated hearts was measured after a 30 min regional ischemia and 120 min reperfusion. Vardenafil (1 nM-1 mM) was infused during reperfusion. HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl ester (TMRE), a fluorescent marker of mitochondrial membrane potential (cm). Key results: Vardenafil at reperfusion reduced infarct size as percentage of the ischemic zone from 45.8 ± 2.0% in control hearts to 26.2 ± 2.7% (Po0.001) only at 10 nM, whereas higher or lower dosages failed to protect. This protective effect was blocked by co-administration of either the GC inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or the PKG inhibitor, KT-5823. HL-1 cardiomyocytes, loaded with TMRE, were treated for 80 min with the calcium ionophore, calcimycin, to induce calcium stress. This reduced the mean cell fluorescence to 63.3 ± 3.8% of baseline values and vardenafil protected against this fall (78.6±3.6%, Po0.01). The vardenafil-induced protection of HL-1 cells was blocked by ODQ, KT-5823 or the PKG-inhibiting peptides DT-2 and DT-3, confirming a role for GC and PKG. Conclusions and implications: These results further support the hypothesis that PDE-5 inhibitors are protective in ischemic hearts, in addition to their known clinical effects in the treatment of erectile dysfunction in men.

Protein Kinase G-dependent Cardioprotective Mechanism of Phosphodiesterase-5 Inhibition Involves Phosphorylation of ERK and GSK3β

“…These results provide a new signaling mechanism underlying the cardioprotective effects of sildenafil and possibly other PDE-5 inhibitors that are currently in use for treatment of ED in men. It is noteworthy that our current results are conceptually supported by a recent study, which demonstrated that another PDE-5 inhibitor, vardenafil, administered at reperfusion in an isolated rat heart model induced cardioprotection against ischemiareperfusion injury through activation of guanylyl cyclase and enhancement of PKG activity (28).…”

An Update on Cardioprotection

“…In the past several years, there has been considerable attention paid to their potential cardioprotective properties, and indeed, there is a growing body of preclinical evidence to support it. The mechanism of PDE5 cardioprotection is complex and beyond the scope of this review, but PDE5 inhibitors appear to be ischemic preconditioning mimetics (87)(88)(89) as well as inhibitors of MPTP formation (90). Other mechanisms may involve reduction in arterial blood pressure (91), attenuation of inotropic responses to catecholamines (92,93), and nitric oxide signaling (94,95).…”

Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality

“…In animal models of myocardial ischaemia and IRI, PDE5i use has reduced infarct size, improved left ventricular performance, suppressed ischaemia-induced arrhythmias and improved animal survival. 12 13 15 28-30 A number of proposed mechanisms for their cardioprotective actions in IRI exist including activation of PKG through the nitric oxide signalling pathway, 31 32 opening of mitochondrial ATP-sensitive potassium channels 28 and stimulation of the sarcolemmal Na+−K+ ATPase pump. 33 In addition to direct myocardial effects, PDE5is may afford protection against endothelial reperfusion injury, 34 improve vascular endothelial function and reduce systemic and pulmonary BP.…”

“…9 This is supported by compelling evidence from animal models indicating that the PDE5is such as sildenafil, tadalafil and vardenafil are cardioprotective in ischaemia-reperfusion injury (IRI) while suppressing cardiac arrhythmias and improving cardiac function. [10][11][12][13][14][15] Furthermore, small randomised controlled trials (RCTs) in systolic heart failure have shown an improvement in haemodynamic parameters and functional indices. 16 It is therefore important to establish whether there is benefit or harm in highrisk patients with ED.…”