title: Cardiac safety profile of sildenafil: chronotropic, inotropic and coronary vasodilator effects in the canine isolated, blood-perfused heart preparations.
abstract: Sildenafil is a phosphodiesterase type-5 inhibitor. We evaluated the effects of sildenafil on the sinoatrial rate, developed tension of the papillary muscle and coronary blood flow by using the canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. The former preparation had a regular automaticity rate of 106 ± 1 beats/min (n = 4), whereas the latter showed a developed tension of 22 ± 4 mN (n = 4) and a coronary blood flow of 3.9 ± 0.1 mL/min (n = 4). Intracoronary injection of 10, 30 and 100 µg of sildenafil, which would provide about 20 to 200 times higher plasma drug concentrations than its therapeutic level, increased the automaticity rate by 4, 12 and 22%, the developed tension by 19, 55 and 118% and the coronary blood flow by 42, 95 and 142%, respectively. These results indicate that supratherapeutic concentration of sildenafil possesses direct positive chronotropic and inotropic effects together with a coronary vasodilator action, confirming that caution has to be paid on the use of sildenafil for patients with ischemic heart diseases, obstructive hypertrophic cardiomyopathy and/or ventricular arrhythmias. The information on sildenafil reported in this study may help establish a guidance on cardiac safety assessment of newer phosphodiesterase type-5 inhibitors.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University.
authors.forename: Nur Jaharat
authors.initials: NJ
authors.lastname: Lubna
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000633:toxicity; D066126:Cardiotoxicity; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D000067268:Isolated Heart Preparation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D018570:Risk Assessment; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000633:toxicity; D012849:Sinoatrial Node / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D002316:Cardiotonic Agents; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate