Mechanisms of the relaxant effect of vardenafil in rat penile arteries.
The aim of the present study was to investigate the mechanisms underlying the vasorelaxation induced by the selective phosphodiesterase 5 (PDE5) inhibitor vardenafil in rat penile small arteries. Segments of the rat dorsal penile artery were mounted in microvascular myographs for isometric tension recording. Concentration-response curves for vardenafil (1 nM-3 microM) and other PDE inhibitors (sildenafil, rolipram and milrinone) were constructed by adding cummulative concentrations of the drugs to arteries precontracted with phenylephrine. The effect of mechanical endothelial cell removal and of selective blockers of the nitric oxide (NO)/cGMP pathway and K+ channels were evaluated on the vardenafil relaxant responses. Vardenafil was the most potent of the four PDE inhibitors tested that maximally relaxed penile arteries, pD2 and maximum relaxation being 6.96+/-0.08 and 97+/-1% (n=48), respectively. Blockade of guanylate cyclase with ODQ (5 microM), mechanical removal of the endothelium or inhibition of NO synthase with l-NOARG (100 microM) markedly reduced vardenafil-induced relaxations, without altering maximum response. Inhibitors of both the cGMP-dependent (PKG) and the cAMP-dependent (PKA) protein kinases, Rp-8-Br-PET-cGMPS (5 microM) and Rp-8-CPT-cAMPS (50 microM), respectively, both reduced vardenafil relaxant responses and the later abolished that of rolipram. Vardenafil-elicited relaxation was reduced by the selective inhibitor of the large-conductance Ca2+-activated K+ channels (BK(Ca)), iberiotoxin (30 nM) and also by the ATP-sensitive K+ channel (K(ATP)) inhibitor, glibenclamide (1 microM). Vardenafil induces a potent vasodilatation in rat penile arteries that is partially dependent on the endothelium and the NO/cGMP pathway and involves activation of both BK(Ca) and K(ATP) channels.
Sánchez
Ana
A
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
Villalba
Nuria
N
Martínez
Ana Cristina
AC
García-Sacristán
Albino
A
Hernández
Medardo
M
Prieto
Dolores
D
D000818:Animals; D001158:Arteries / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology; D010413:Penis / Q000098:blood supply* / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; D020889:Rolipram