title: Pharmacological postconditioning by bolus injection of phosphodiesterase-5 inhibitors vardenafil and sildenafil.
abstract: Postconditioning enables cardioprotection against ischemia/reperfusion injury either by application of short, repetitive ischemic periods or by pharmacological intervention prior to reperfusion. Pharmacological postconditioning has been described for phosphodiesterase-5 inhibitors when the substances were applied as a permanent infusion. For clinical purposes, application of a bolus is more convenient. In a rat heart in situ model of ischemia reperfusion vardenafil or sildenafil were applied as a bolus prior to reperfusion. Cardioprotective effects were found over a broad dosage range. In accordance with current hypotheses on pharmacological postconditioning signaling, the protective effect was mediated by extracellular signal-regulated kinase and protein kinase C pathway. Interestingly, the extent of protection was independent of the concentration applied for both substances. Full protection comparable to ischemic postconditioning was reached with half-maximal human equivalence dose. In contrast, mean arterial pressure dropped upon bolus application in a dose-dependent manner. Taken together, the current study extends previous findings obtained in a permanent infusion model to bolus application. This is an important step toward clinical application of pharmacological postconditioning with sildenafil and vardenafil, especially because the beneficial effects were proven for concentrations with reduced hemodynamic side effects compared to the dosage applied for erectile dysfunction treatment.
authors.affiliation: Department of Medicine/Cardiology, Heart Center Dresden, University Hospital, University of Technology Dresden, Dresden, Germany. bernd_ebner@web.de
authors.forename: Bernd
authors.initials: B
authors.lastname: Ebner
authors.forename: Annette
authors.initials: A
authors.lastname: Ebner
authors.forename: Anna
authors.initials: A
authors.lastname: Reetz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Böhme
authors.forename: Antje
authors.initials: A
authors.lastname: Schauer
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.forename: Christof
authors.initials: C
authors.lastname: Weinbrenner
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage* / Q000494:pharmacology; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D002316:Cardiotonic Agents; D005419:Flavonoids; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D006152:Cyclic GMP; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one