Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury

Abstract

The ability of pharmacological preconditioning mimetics to confer long-lasting and sustained cardioprotection may be a logical criterion to develop a drug that can be used clinically for cardioprotection. We propose here that the use of long-acting phosphodiesterase-5 inhibitor, tadalafil, may confer sustained cardioprotection against ischemia. Tadalafil (5 mg/kg) was administered orally to male C57B/6J mice (n = 6 in each treatment subgroup at each time point studied). Hearts were isolated and subjected to 40 min of ischemia and 30 min of reperfusion on Langendorff's apparatus at 1, 12, 24, 36, 48, 60, 72, and 108 h after tadalafil administration. In 1- to 48-h subgroups, tadalafil was given once at 0 h only. In 60- and 72-h subgroups, tadalafil was given twice at 0 and 36 h. Similarly, in the 108-h subgroup, tadalafil was administered at 0, 36, and 72 h. In the same subgroups, wortmannin (15 microg/kg ip), an inhibitor of phosphatidylinositol 3-kinase or 5-hydroxydecanoic acid (5 mg/kg ip), an inhibitor of mitochondrial ATP-sensitive K(+) channels, was given together with tadalafil, and the hearts were subjected to ischemia-reperfusion at 36 h to determine whether the effect of tadalafil on ischemia-reperfusion injury was abolished. As a result, tadalafil treatment reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced lactate dehydrogenase release. This protection remained till 36-40 h, and thereafter it vanished. The readministration of tadalafil at 36 and 72 h restored the protection till 108 h. Tadalafil treatment accelerated Akt phosphorylation in cardiac tissue and decreased myocyte apoptosis. The administration of wortmannin abolished the beneficial effects of tadalafil on hemodynamic parameters and myocyte apoptosis, together with significantly reduced Akt phosphorylation. 5-Hydroxydecanoic acid also abolished the antiapoptotic effect of tadalafil. It is concluded that tadalafil treatment induces the long-term protection of ischemic myocardium via phosphatidylinositol 3-kinase/Akt signaling pathway.

Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells

“…More importantly, the cytoprotective effects of one-time treatment of the cells with tadalafil were extended to at least 36 h after treatment. We have already shown in vivo that repeated administration of tadalafil at regular intervals of 48 h extended the cardioprotective effects of tadalafil treatment (2). In the light of these results, our present study extrapolated the prolonged prosurvival and proproliferative effects of tadalafil in MSCs via cGMP/PKG signaling.…”

“…Tadalafil belongs to the group of long-acting PDE5 inhibitors and protects the ischemic heart for extended time duration (2). We have already shown that tadalafil administration reduced left ventricular (LV) end-diastolic pressure and increased LV developed pressure besides reducing cardiomyocyte injury through its cytoprotective effects.…”

“…We have already shown that tadalafil administration reduced left ventricular (LV) end-diastolic pressure and increased LV developed pressure besides reducing cardiomyocyte injury through its cytoprotective effects. This protection persisted for 36 h, and a subsequent readministration of tadalafil at 36 and 72 h restored the protection until 108 h, with a possible role of protein kinase B (Akt) signaling (2). PDE inhibitors have been extensively used for treatment of heart failure, pulmonary hypertension, and coronary artery disease besides their use for the treatment of erectile dysfunction (3,12,16,23).…”

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

“…Conversely, single-dose administration of the longacting tadalafil was reported to have variable effects on blood pressure. The applied dose of tadalafil, 4 mg/kg via gastric delivery, was approximated from human studies and was reported to reach protective plasma concentrations in rodents (Sesti et al, 2007;Ahmad et al, 2009;Salloum et al, 2009Salloum et al, , 2014Koka et al, 2014). In this study, monotherapy with iNO and TAD or combined application did not compromise blood pressure, one of the most critical parameters during I/R treatment protocols.…”

“…Dose and timing of NO inhalation was selected on the basis of previously reported results (Hataishi et al, 2006). Tadalafil (Kemprotec Ltd., Cumbria, UK) dissolved in 30% solution of 2-hydroxypropyl-b-cyclodextrin (SigmaAldrich, St. Louis, MO) was administered via gastric gavage (4 mg/kg) 1 hour prior to I/R, which was determined on the basis of previously reported interspecies dose extrapolations (Ahmad et al, 2009;Salloum et al, 2009;Koka et al, 2010). To determine acute cardiac cGMP responses to myocardial ischemia during different treatment regimens, an additional subset of animals (n 5 6-8 per treatment arm) was euthanized 20 minutes after reperfusion (Fig.…”