Search

Background and purpose:Phosphodiesterase type-5 (PDE5) inhibitors constitute a novel and important therapeutic option for the treatment of pulmonary hypertension. The effects of the PDE5 inhibitors sildenafil, tadalafil and vardenafil on rabbit isolated pulmonary artery ring preparations and on intracellular Ca2+ concentration of thrombin-stimulated human platelets were investigated.Experimental approach:Rabbit pulmonary artery rings were mounted in 10 mL organ bath containing Krebs solution. Tissues were connected to force-displacement transducers, and changes in isometric force were recorded. Ca2+ flux in human washed platelets was measured.Key results:Sildenafil, tadalafil and vardenafil (0.0001–10 μM) concentration-dependently relaxed endothelium-intact and endothelium-denuded pulmonary artery rings. Endothelium denudation caused rightward shifts in the concentration–response curves to sildenafil, tadalafil and vardenafil (9-, 12- and 123-fold, respectively). Incubation with Nω-nitro-L-arginine methyl ester (100 μM) or ODQ (1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one) (10 μM) caused similar reductions of PDE5-induced vasorelaxations in intact rings. Sildenafil and tadalafil did not affect the phenylephrine-induced contractions, whereas vardenafil reduced the maximal responses, and shifted the phenylephrine-induced contraction curves to the right in endothelium-denuded rings (5- and 19-fold for 1 and 10 μM, respectively). Vardenafil (but neither sildenafil nor tadalafil) caused a marked rightward shift and a decrease of maximal contractile response to CaCl2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca2+ mobilization and Ca2+ influx in thrombin-stimulated washed platelets.Conclusions and implications:Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.British Journal of Pharmacology (2008) 154, 787–796; doi:10.1038/bjp.2008.141; published online 21 April 2008 [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the influence of run training on the responsiveness of corpus cavernosum (CC) from rats made hypertensive by treatment with nitric oxide (NO) synthesis inhibitor. Wistar rats were divided into sedentary control (C-SD), exercise training (C-TR), Nω-nitro-L-arginine methyl ester (L-NAME) sedentary (LN-SD) and L-NAME trained (LN-TR) groups. The run training program consisted in 8 weeks in a treadmill, 5 days/week, each session lasted 60 min. L-NAME treatment (2 and 10 mg/rat/day) started after 4 weeks of prior physical conditioning and lasted 4 weeks. Concentration–response curves were obtained for acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil and BAY 41-2272. The effect of electrical field stimulation (EFS) on the relaxations responses of CC was evaluated. Run training prevented the arterial hypertension induced by L-NAME treatment (LN-SD: 135±2 and 141±2 mm Hg for both doses of L-NAME) compared to LN-SD groups (154±1 and 175±2 mm Hg, for 2 and 10 mg of L-NAME, respectively). Run training produced an increase in the maximal responses (Emax) of CC for ACh (C-SD: 47±3; C-TR: 52±1; and LN-TR: 53±3%) and SNP (C-SD: 89±1; C-TR: 98±1; and LN-TR: 95±1%). Both potency and Emax for ACh were reduced in a dose of 10 mg of L-NAME, and run training restored the reduction of Emax for ACh. No changes were found for BAY 41-2271 and sildenafil. Relaxing responses to EFS was reduced by L-NAME treatment that was restored by prior physical conditioning. In conclusion, our study shows a beneficial effect of prior physical conditioning on the impaired CC relaxing responses in rats made hypertensive by chronic NO blockade.International Journal of Impotence Research (2007) 19, 189–195. doi:10.1038/sj.ijir.3901511; published online 17 August 2006 [ABSTRACT FROM AUTHOR]