Inhibition of sympathetic neuroeffector transmission in human corpus cavernosum

Serap Gur, Philip J. Kadowitz, Suresh C. Sikka, Trinity J. Bivalacqua, Wayne J.G. Hellstrom

Research output: Contribution to journalArticlepeer-review

Abstract

Objective To investigate the mechanisms of adrenergically mediated smooth muscle contraction in the human corpus cavernosum (HCC) using an organ bath approach. Methods Human corpus cavernosum specimens were obtained from patients (aged 59-72 years) with erectile dysfunction (ED), undergoing penile prosthesis implantation surgery. Isolated HCC strips (1 × 1 × 6 mm) were suspended in tissue bath chambers for isometric tension recording. The effects of various drugs on neurogenic contractions evoked by electrical field stimulation (EFS) were investigated. The drugs included nitric oxide (NO) donors, phosphodiesterase 5 (PDE5) inhibitor, Rho kinase (ROCK) inhibitor, NO-independent stimulator, L-type Ca2+ channel blocker and α-receptor antagonist. Results Pre-incubation with the NO donor sodium nitroprusside (SNP; 10 4 M) significantly reduced the initial peak increase in tension evoked by EFS (by 71%, P < 0.05). The PDE5 inhibitor sildenafil (10 -4 M) reduced the increase in tension by 69%, while a combination of sildenafil and ROCK inhibitor, fasudil, inhibited tension by 81%. The EFS-induced contractile response at 80 Hz was decreased by 65% with fasudil and by 70% with isradipine (P < 0.001), while a combination of these drugs decreased the response by 88%. An NO-independent stimulator soluble guanylate cyclase (sGC), BAY 41-8543, significantly reduced the response (by 82%, P < 0.001) Phentolamine, an α-receptor antagonist, nearly eliminated the contractile response (98%, P < 0.001). CONCLUSIONS These data suggest that neurogenic contractions are mediated by an increase in Ca(2+) influx via L-type voltage-gated Ca(2+) channels and that an increase in Ca(2+) sensitivity is mediated by the ROCK pathway and the PDE5 enzyme system as well as by the inhibitory NO/sGC/cGMP pathway. The neurogenic contractile response in HCC is mediated by several intracellular pathways, including adrenergic receptors, Ca(2+) entry, Ca(2+) sensitization and activation of the PDE5 enzyme. The Rho-kinase (ROCK) inhibitor fasudil, L-type Ca(2+) channel antagonist isradipine, and PDE5 inhibitor sildenafil, as well as a NO-independent stimulator of sGC, had similar inhibitory effects, suggesting parallel mechanisms in the HCC.

Original languageEnglish (US)
Pages (from-to)856-862
Number of pages7
JournalBJU International
Volume110
Issue number6
DOIs
StatePublished - Sep 2012

Keywords

  • ROCK pathway
  • adrenergic neurotransmission
  • fasudil
  • human corpus cavernosum
  • nitric oxide
  • sildenafil

ASJC Scopus subject areas

  • Urology

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