Relaxant effect of sildenafil in the rabbit basilar artery.
We hypothesized that sildenafil, inhibitor of phosphodiesterase-5 (PDE-5), interacts with the nitric oxide (NO)-cGMP pathway in the cerebral arteries and shows vasoactive effects. To prove it in the isolated rabbit basilar artery, we compared the effects of sildenafil with other PDE-5 inhibitors, assessed the endothelial dependence of the vasoactive responses, and used modulators of the cGMP and cAMP signaling processes. Sildenafil (10 nM-0.1 mM) induced concentration-dependent relaxations of endothelin-1 (10 nM)-precontracted basilar artery, which were partially inhibited both in endothelium-denuded arteries and in arteries precontracted by depolarization with KCl (50 mM). Endothelin-1 (1 pM-30 nM) induced concentration-dependent contractions that were inhibited by sildenafil (0.1-100 microM). Zaprinast (10 nM-0.1 mM) and MBCQ (1 nM-0.1 mM), PDE-5 inhibitors, induced concentration-dependent relaxations with lower and higher potency than sildenafil, respectively. Sildenafil-induced relaxation was inhibited in arteries preincubated with the NO synthase inhibitor L-NAME (0.1 mM) or the soluble guanylyl cyclase inhibitor ODQ (10 microM). Preincubation with sildenafil (0.1 microM) enhanced the relaxations induced by acetylcholine (0.1 nM-0.1 mM) and the NO donor sodium nitroprusside (0.1 nM-0.1 mM), but not those induced by the cell-permeable cGMP analogue 8-Br-cGMP (1 nM-0.1 mM) and the adenylyl cyclase activator forskolin (0.1 nM-10 microM). These results show that sildenafil has vasoactive effects in isolated cerebral arteries. By enhancing the NO-cGMP signaling pathway in the cerebrovascular wall, sildenafil induces vasodilation, prevents vasoconstriction, and potentiates the effect of other NO-dependent vasodilators.
Salom
Juan B
JB
Centro de Investigación, Hospital Universitario La Fe, Ave. Campanar 21, 46009 Valencia, Spain. salom_jba@gva.es
Burguete
María C
MC
Pérez-Asensio
Fernando J
FJ
Castelló-Ruiz
María
M
Torregrosa
Germán
G
Alborch
Enrique
E
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000201:enzymology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester