Differential Effects of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Vardenafil, and Tadalafil in Rat Aorta

Abstract

Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 M) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 Ϯ 1% and 53 Ϯ 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N -nitro-Larginine methyl ester, 100 M), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 M), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 M]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 M; 8 -13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl 2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 Ϯ 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca 2ϩ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation

“…Rat aorta rings pretreated with adrenergic agonists suggest that vardenafil, but not sildenafil or tadalafil, affects Ca (2 þ ) handling, in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation. 28 Further studies confirmed that vardenafil, in contrast to sildenafil or tadalafil, is able to block Ca 2 þ fluxes, thus enhancing vasorelaxation of the rabbit pulmonary artery. 29 …”

Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

“…One such mechanism is the blockade of the calcium channels, which has been demonstrated for some other PDE-5 inhibitors. [15][16][17] Another possibility is an increased expression of endothelial NO synthase 18,19 or inhi- bition of superoxide formation, 20 although this latter effect is cGMP dependent.…”

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

“…The effects of PDE5 inhibitors have already been demonstrated with sildenafil (21,22) approved for PAH indication, but the effects of tadalafil on PAH may not be equivalent because they have different pharmacokinetics and selectivity to the PDEs (23). Different effects among the specific PDE5 inhibitors (sildenafil, vardenafil, and tadalafil) have been reported on the calcium handling in aorta (24) and pulmonary artery cytokine expression (25). The purpose of this study, therefore, was to investigate the potential effects of tadalafil on PAH progression and on survival benefit using the monocrotaline (MCT)-induced PAH rat model.…”