The present study showed that administering vardenafil at reperfusion decreased infarct size in rat isolated hearts. Although vardenafil was protective at 10nM, we were surprised to find that the protective effect was lost at higher concentrations. So far, we have no explanation for this observation. We could show that protection by vardenafil at 10nM was dependent on the activity of GC and the cGMP-dependent kinase PKG. Furthermore, vardenafil was found to be protective in a model of TMRE-stained cardiomyocytes exposed to calcium stress with a selective calcium ionophore. The cell model allowed the additional use of the highly specific PKG inhibitory peptides DT-2 and DT-3 to further support a role for PKG.
Archive for the ‘Main’ Category
Infarct size measurements
No significant differences in coronary flow at baseline and during occlusion among the experimental groups were observed (Table 1). Coronary flow at 5min of reperfusion was significantly increased only in the group treated with 1μM vardenafil (P=0.008). All other groups showed no significant increase in coronary flow at reperfusion, including the protective group with vardenafil at 10nM.
Rat isolated heart model
Female Wistar rats (180–200g; total of 52) were anaesthetized with pentobarbital sodium (60mgkg−1 i.p.), and hearts were excised, mounted on a Langendorff apparatus and perfused in a constant pressure mode with modified Krebs–Henseleit bicarbonate buffer containing (mM) 118.5 NaCl, 24.8 NaHCO3, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 2.5 CaCl2 and 10 glucose. A suture was passed around a major branch of the left coronary artery. After equilibration, hearts were subjected to 30min of regional ischemia by occluding the snared artery followed by 2h of reperfusion as depicted in Figure 1. Control hearts were subjected to only 30min of regional ischemia and then reperfusion. Four groups of hearts were treated with different vardenafil dosages (1, 10, 100 and 1000nM) during the reperfusion period starting 5min before reperfusion. In the next groups, one of three inhibitors was co-infused along with the protective vardenafil dose of 10nM. These inhibitors included the GC inhibitor ODQ (10μM) and the PKG inhibitor KT-5823 (1μM). Finally, three groups of hearts were treated with only ODQ or KT-5823, as noted above, to exclude independent effects of the blockers.
Recent studies have implicated that PDE-5 inhibitors, such as sildenafil, vardenafil or tadalafil, induce preconditioning-like effects in the heart and protect against ischemia/reperfusion injury. PDE-5 inhibition has been shown to enhance the accumulation of the cyclic nucleotide cGMP, which in turn acts as a second messenger in many signaling events in healthy and diseased myocardium. Intracardiac cGMP is produced by two isoforms of GC: particulate GC, which is activated by natriuretic peptides (atrial, brain and C-type natriuretic peptides) and soluble GC, which is activated by nitric oxide. On GC activation, cGMP accumulates and interacts with several targets, including the cGMP-dependent PKG. The cGMP/PKG pathway has been shown in many reports to be involved in the protective signaling of preconditioning, for example, direct PKG activation with a cell-permeant cGMP analogue proved to be protective, as well as receptor-mediated preconditioning could be blocked with the GC inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). Therefore, it seems only logical that PDE-5 inhibitors would protect the heart against ischemia/reperfusion injury when administered before ischemia. A detailed summary of the attenuation of increased cGMP during ischemia/reperfusion can be found in a recent review from Burley et al. Although there is increasing evidence that the heart is protected against ischemia/reperfusion injury due to elevated cGMP or PKG activity, considerably less is known whether this is exclusively related to myocytes or other compartments (for example, endothelium) play a partial or even major role.
The efficacy of phosphodiesterase type 5 (PDE5) inhibitors in restoring erectile function in men with erectile dysfunction (ED) has been evaluated primarily by means of patient-reported outcome measures, including questionnaires and performance scoring.
This is the first clinical study in which a stopwatch approach was used to measure accurately the duration of erection as it pertains to successful intercourse during PDE5 inhibitor therapy. Results demonstrate that treatment with vardenafil (Levitra) is associated with an increased duration of erection and restoration of erectile function compared with placebo.