Inhibitors of phosphodiesterase 5 (PDE 5) inhibit the nerve-induced release of nitric oxide from the rabbit corpus cavernosum.
OBJECTIVE
Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue.


METHODS
Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence.


RESULTS
Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72+/-11%, 55+/-16% and 61+/-14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) M, n=6-8, p<0.05).


CONCLUSIONS
Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.
Hallén
K
K
Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Hospital, Stockholm, Sweden. katarina.hallen@fyfa.ki.se
Wiklund
N P
NP
Gustafsson
L E
LE
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D026602:Nitrergic Neurons / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010413:Penis / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011317:Priapism / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP