The experiments of new treatment on sildenafil citrate non-responders in erectile dysfunction patients

• Project/Area Number: 16591625
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Toho University
• Principal Investigator: ISHII Nobuhisa Toho University, School of Medicine, Professor, 医学部, 教授 (10111270)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: erectile dysfunction / sildenafil citrate / prostaglandin E1 / EP2 receptor agonist / EP4 receptor agonist / phosphodiesterase type-V / protein kinase G / Rho kinase / protein kinase A / phosphodiesterase type-III / EP2作用薬 / EP4作用薬

Research Abstract

The erection is caused by the relaxation of the corpus cavernosum (CC). The mechanisms of relaxation in the CC smooth muscle is shown by the elevation of protein kinase G (PKG) activity following the increase of cGMP production induced by guanylate cyclase (GCase). Nitric oxide (NO), which is synthesized by nitric oxide synthase (NOS) inendothelium and/or nitrergicnerve, participated this response. The response to NO induced by several stimulations is potentiated by sildenafil, inhibitor of phosphodiesterase type-V, which is catabolic enzyme of cGMP. The prostaglandin E_1 (PGE_1)-induced erection is caused by the activation of adenylate cyclase-cAMP-PKA system. The aim of this experiment is to develop the new cure for sildenafil non-responder. We studied effects of L-NAME, NOS inhibitor, ODQ, soluble GCase inhibitor, and KT5823, PKG inhibitor, on relaxations induced by electrical field stimulation (EFS : 2.5-40Hz), sodium nitroprusside (SNP), PGE_1, PGE_2, EP1 agonist and EP2 agonist. Additionally, we studied influences to PDE-V antibody and Y27632, Rho kinase inhibitor, on the CC. The EFS-induced relaxation was suppressed by L-NAME but not SNP-induced one. ODQ suppressed EFS- and SNP-induced relaxations but not PGE_1-, PGE_2-, EP1 agonist- and EP2 agonist-induced those. KT5823 did not cause any effect on the EFS- and SNP-induced relaxations. Y27632 relaxed the CC. The CC isolated from rabbit treated by PDE-V antibody showed the decrease of spontaneous and rhythmical contraction and the potentiation of the relaxation induced by EFS. These results suggested that possibility of participation of other mechanism except downstream through PKG in the cGMP-induced relaxation. The fact that Y27632 caused relaxation in the CC would be connected with the development of new drug for erectile dysfunction, if the specific isozyme of Rho kinase will be discovered in the CC. There is possibility that intracavernous injection of PDE-V antibody is effective for sildenafil non-responder.