Cardiac electrophysiologic and hemodynamic effects of sildenafil, a PDE5 inhibitor, in anesthetized dogs.
A recent in vitro study demonstrated that supratherapeutic concentrations of sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, blocked I(Kr) and prolonged cardiac repolarization. This study assessed the in vivo cardiohemodynamic and electrophysiologic effects of sildenafil using a halothane-anesthetized, closed-chest canine model (n = 5) to bridge the gap between basic observation and clinical experience. Intravenous administration of sildenafil citrate in doses of 0.03, 0.3, and 3.0 mg/kg for 10 min, which provided sub-to supratherapeutic plasma drug concentrations, did not affect the monophasic action potential duration or effective refractory period of the right ventricle during the sinus rhythm as well as the ventricular pacing at the cycle length of 400 and 300 ms. However, sildenafil decreased the total peripheral resistance, simultaneously inducing positive chronotropic and inotropic effects at the top dose, which gave plasma concentrations at least 10 times higher than the therapeutic range. This cardiohemodynamic profile of sildenafil can be largely explained by reflex sympathetic activation associated with its vasodilator effect. Meanwhile, the lack of prolongation of the ventricular repolarization phase at the therapeutically relevant to moderately supratherapeutic sildenafil concentrations supports the earlier clinical studies that indicate that sildenafil has no effect on electrocardiogram.
Sugiyama
A
A
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakanoma-gun, Yamanashi, 409-3898, Japan. atushis@res.yamanashi-med.ac.jp
Satoh
Y
Y
Shiina
H
H
Takahara
A
A
Yoneyama
M
M
Hashimoto
K
K
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002036:Bundle of His / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004553:Electric Conductivity; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000494:pharmacology*; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D011687:Purines; D012032:Refractory Period, Electrophysiological; D000068677:Sildenafil Citrate; D013450:Sulfones; D014655:Vascular Resistance / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5