Inhibition of sympathetic neuroeffector transmission in human corpus cavernosum

Authors


Wayne J.G. Hellstrom, Section of Andrology, Tulane University, Health Sciences Center, Department of Urology, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA. e-mail: whellst@tulane.edu

Abstract

Study Type – Aetiology (case control)

Level of Evidence 2b

What's known on the subject? and What does the study add?

In the present study the mechanisms regulating EFS-evoked neurogenic contraction in the human corpus cavernosum (HCC) were investigated. Overall, our data adds to current knowledge that the NO-independent heme dependent activation of sGC and the RhoA/Rho-kinase signaling pathways play an important role in the regulation of neurogenic contractile activity in HCC tissue.

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; 104 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.

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