Potentiation of penile tumescence by T-1032, a new potent and specific phosphodiesterase type V inhibitor, in dogs.
We examined the mechanism underlying the potentiation of penile tumescence by methyl 2-(4-aminophenyl)-1, 2dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)3-isoquinoline carboxylate sulfate (T-1032), a new potent and selective phosphodiesterase type V inhibitor. In vivo, pelvic nerve stimulation induced a penile tumescence together with increase of total nitric oxide metabolite levels within the corpus cavernosa of anesthetized dogs. Intravenous (1-100 microg/kg) and intraduodenal (3, 30, 300 microg/kg) treatment with T-1032 dose dependently potentiated the tumescence. The potency of T-1032 was equivalent to that of sildenafil. T-1032 did not influence the intracavernous pressure when the pelvic nerve stimulation was absent. The potentiation of tumescence was more pronounced by intracavernous than i.v. injection. Intracavernous N(G)-nitro-L-arginine, a nitric-oxide synthase inhibitor, but not N(G)-nitro-D-arginine diminished the effects of T-1032 on the tumescence. Furthermore, i.v. T-1032 augmented the tumescence induced by sodium nitroprusside (SNP) but not by vasoactive intestinal polypeptide (VIP). In vitro, in isolated preparations of canine corpus cavernosum precontracted with phenylephrine, SNP (0. 01-100 microM) and VIP (0.01-1 microM) produced a dose-dependent relaxation accompanied by an increase in cGMP and cAMP levels, respectively. T-1032 augmented the relaxation induced by SNP but not by VIP. These data suggest that oral treatment with T-1032 has potential to improve erectile dysfunction through the inhibition of phosphodiesterase type V in the smooth muscles of corpus cavernosa.
Noto
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Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan. t-noto@tanabe.co.jp
Inoue
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Ikeo
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Kikkawa
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D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019335:Nitroarginine / Q000737:chemistry / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011725:Pyridines / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D013237:Stereoisomerism; D013450:Sulfones; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011725:Pyridines; D013450:Sulfones; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D006152:Cyclic GMP; C412889:T 1032