Cardiac safety profile of sildenafil: chronotropic, inotropic and coronary vasodilator effects in the canine isolated, blood-perfused heart preparations

摘要

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 ug 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.