Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits.
Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.
Shukla
Nilima
N
Bristol Heart Institute, Department of Cardiac Surgery, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
Jones
Robert
R
Persad
Raj
R
Angelini
Gianni D
GD
Jeremy
Jamie Y
JY
D000098:Acetophenones / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010413:Penis / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D012402:Rotenone / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones; D013481:Superoxides / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000098:Acetophenones; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009861:Onium Compounds; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; D014475:Uncoupling Agents; D012402:Rotenone; D013481:Superoxides; D009599:Nitroprusside; D000493:Allopurinol; C007517:diphenyleneiodonium; D002217:Carbachol; C056165:acetovanillone; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester