Received for publication July 14, 2005.
Revised October 1, 2005.
Accepted for publication October 3, 2005.

Differential effects of the phosphodiesterase type-5 inhibitors sildenafil, vardenafil and tadalafil in rat aorta

Abstract

Presumably, the vasorelaxant properties of 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 µM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and denuded rings. Cyclic nucleotides were measured using EIA 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 ± 1% and 53 ± 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (L-NAME, 100 µM), guanylyl cyclase (ODQ, 10 µM) or scavenging of NO (carboxy-PTIO, 100 µM) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (GTN, 0.0001-3 µM; 8-13-fold) and atrial natriuretic peptide (ANP, 0.1-100 nM; 2-3-fold). Contractions evoked by CaCl₂ (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 4%) by vardenafil, but not sildenafil or tadalafil, whereas PDBu-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 Ca²⁺ handling in the rat aorta besides increasing cGMP levels through inhibition of PDE5 to cause relaxation.

Key words: Phosphodiesterase type-5, cyclic GMP, nitric oxide, sildenafil, tadalafil, vardenafil

This article has been cited by other articles:

				M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]

				D. A. Kass Hypertrophied Right Hearts Get Two for the Price of One: Can Inhibiting Phosphodiesterase Type 5 Also Inhibit Phosphodiesterase Type 3? Circulation, July 17, 2007; 116(3): 233 - 235. [Full Text] [PDF]