Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue

Kenia P. Nunes, Marta N. Cordeiro, Michael Richardson, Marcia N. Borges, Simone O.F. Diniz, Valbert N. Cardoso, Rita Tostes, Maria Elena De Lima, R Clinton Webb, Romulo Leite

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Introduction. Priapism is one of several symptoms observed in accidental bites by the spider Phoneutria nigriventer. The venom of this spider is comprised of many toxins, and the majority has been shown to affect excitable ion channels, mainly sodium (Na+) channels. It has been demonstrated that PnTx2-6, a peptide extracted from the venom of P. nigriventer, causes erection in anesthetized rats and mice.Aim. We investigated the mechanism by which PnTx2-6 evokes relaxation in rat corpus cavernosum.Main Outcome Measures. PnTx2-6 toxin potentiates nitric oxide (NO)-dependent cavernosal relaxation.Methods. Rat cavernosal strips were incubated with bretylium (3 × 10-5 M) and contracted with phenylephrine (PE; 10-5 M). Relaxation responses were evoked by electrical field stimulation (EFS) or sodium nitroprusside (SNP) before and after 4 minutes of incubation with PnTx2-6 (10-8 M). The effect of PnTx2-6 on relaxation induced by EFS was also tested in the presence of atropine (10-6 M), a muscarinic receptor antagonist, N-type Ca2+ channel blockers (ω-conotoxin GVIA, 10-6 M) and sildenafil (3 × 10-8 M). Technetium99m radiolabeled PnTx2-6 subcutaneous injection was administrated in the penis.Results. Whereas relaxation induced by SNP was not affected by PnTx2-6, EFS-induced relaxation was significantly potentiated by this toxin as well as PnTx2-6 plus SNP. This potentiating effect was further increased by sildenafil, not altered by atropine, however was completely blocked by the N-type Ca2+ channels. High concentrated levels of radiolabeled PnTx2-6 was specifically found in the cavernosum tissue, suggesting PnTx2-6 is an important toxin responsible for P. nigriventer spider accident-induced priapism.Conclusion. We show that PnTx2-6 slows Na+ channels inactivation in nitrergic neurons, allowing Ca2+ influx to facilitate NO/cGMP signalling, which promotes increased NO production. In addition, this relaxation effect is independent of phosphodiesterase enzyme type 5 inhibition. Our data displays PnTx2-6 as possible pharmacological tool to study alternative treatments for erectile dysfunction.

Original languageEnglish (US)
Pages (from-to)3879-3888
Number of pages10
JournalJournal of Sexual Medicine
Volume7
Issue number12
DOIs
StatePublished - Jan 1 2010

Fingerprint

Spiders
Nitroprusside
Vasodilation
Electric Stimulation
Priapism
Nitric Oxide
Atropine
Nitrergic Neurons
Spider Bites
Spider Venoms
Conotoxins
Type 5 Cyclic Nucleotide Phosphodiesterases
Data Display
Muscarinic Antagonists
Sodium Channels
Penis
Venoms
Phenylephrine
Muscarinic Receptors
Erectile Dysfunction

Keywords

  • Corpus Cavernosum
  • Erectile Physiology
  • Nitric Oxide
  • PnTx2-6 Toxin
  • Relaxation

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Urology

Cite this

Nunes, K. P., Cordeiro, M. N., Richardson, M., Borges, M. N., Diniz, S. O. F., Cardoso, V. N., ... Leite, R. (2010). Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue. Journal of Sexual Medicine, 7(12), 3879-3888. https://doi.org/10.1111/j.1743-6109.2010.01978.x

Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue. / Nunes, Kenia P.; Cordeiro, Marta N.; Richardson, Michael; Borges, Marcia N.; Diniz, Simone O.F.; Cardoso, Valbert N.; Tostes, Rita; De Lima, Maria Elena; Webb, R Clinton; Leite, Romulo.

In: Journal of Sexual Medicine, Vol. 7, No. 12, 01.01.2010, p. 3879-3888.

Research output: Contribution to journalArticle

Nunes, KP, Cordeiro, MN, Richardson, M, Borges, MN, Diniz, SOF, Cardoso, VN, Tostes, R, De Lima, ME, Webb, RC & Leite, R 2010, 'Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue', Journal of Sexual Medicine, vol. 7, no. 12, pp. 3879-3888. https://doi.org/10.1111/j.1743-6109.2010.01978.x
Nunes, Kenia P. ; Cordeiro, Marta N. ; Richardson, Michael ; Borges, Marcia N. ; Diniz, Simone O.F. ; Cardoso, Valbert N. ; Tostes, Rita ; De Lima, Maria Elena ; Webb, R Clinton ; Leite, Romulo. / Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue. In: Journal of Sexual Medicine. 2010 ; Vol. 7, No. 12. pp. 3879-3888.
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T1 - Nitric oxide-induced vasorelaxation in response to pntx2-6 toxin from phoneutria nigriventer spider in rat cavernosal tissue

AU - Nunes, Kenia P.

AU - Cordeiro, Marta N.

AU - Richardson, Michael

AU - Borges, Marcia N.

AU - Diniz, Simone O.F.

AU - Cardoso, Valbert N.

AU - Tostes, Rita

AU - De Lima, Maria Elena

AU - Webb, R Clinton

AU - Leite, Romulo

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Introduction. Priapism is one of several symptoms observed in accidental bites by the spider Phoneutria nigriventer. The venom of this spider is comprised of many toxins, and the majority has been shown to affect excitable ion channels, mainly sodium (Na+) channels. It has been demonstrated that PnTx2-6, a peptide extracted from the venom of P. nigriventer, causes erection in anesthetized rats and mice.Aim. We investigated the mechanism by which PnTx2-6 evokes relaxation in rat corpus cavernosum.Main Outcome Measures. PnTx2-6 toxin potentiates nitric oxide (NO)-dependent cavernosal relaxation.Methods. Rat cavernosal strips were incubated with bretylium (3 × 10-5 M) and contracted with phenylephrine (PE; 10-5 M). Relaxation responses were evoked by electrical field stimulation (EFS) or sodium nitroprusside (SNP) before and after 4 minutes of incubation with PnTx2-6 (10-8 M). The effect of PnTx2-6 on relaxation induced by EFS was also tested in the presence of atropine (10-6 M), a muscarinic receptor antagonist, N-type Ca2+ channel blockers (ω-conotoxin GVIA, 10-6 M) and sildenafil (3 × 10-8 M). Technetium99m radiolabeled PnTx2-6 subcutaneous injection was administrated in the penis.Results. Whereas relaxation induced by SNP was not affected by PnTx2-6, EFS-induced relaxation was significantly potentiated by this toxin as well as PnTx2-6 plus SNP. This potentiating effect was further increased by sildenafil, not altered by atropine, however was completely blocked by the N-type Ca2+ channels. High concentrated levels of radiolabeled PnTx2-6 was specifically found in the cavernosum tissue, suggesting PnTx2-6 is an important toxin responsible for P. nigriventer spider accident-induced priapism.Conclusion. We show that PnTx2-6 slows Na+ channels inactivation in nitrergic neurons, allowing Ca2+ influx to facilitate NO/cGMP signalling, which promotes increased NO production. In addition, this relaxation effect is independent of phosphodiesterase enzyme type 5 inhibition. Our data displays PnTx2-6 as possible pharmacological tool to study alternative treatments for erectile dysfunction.

AB - Introduction. Priapism is one of several symptoms observed in accidental bites by the spider Phoneutria nigriventer. The venom of this spider is comprised of many toxins, and the majority has been shown to affect excitable ion channels, mainly sodium (Na+) channels. It has been demonstrated that PnTx2-6, a peptide extracted from the venom of P. nigriventer, causes erection in anesthetized rats and mice.Aim. We investigated the mechanism by which PnTx2-6 evokes relaxation in rat corpus cavernosum.Main Outcome Measures. PnTx2-6 toxin potentiates nitric oxide (NO)-dependent cavernosal relaxation.Methods. Rat cavernosal strips were incubated with bretylium (3 × 10-5 M) and contracted with phenylephrine (PE; 10-5 M). Relaxation responses were evoked by electrical field stimulation (EFS) or sodium nitroprusside (SNP) before and after 4 minutes of incubation with PnTx2-6 (10-8 M). The effect of PnTx2-6 on relaxation induced by EFS was also tested in the presence of atropine (10-6 M), a muscarinic receptor antagonist, N-type Ca2+ channel blockers (ω-conotoxin GVIA, 10-6 M) and sildenafil (3 × 10-8 M). Technetium99m radiolabeled PnTx2-6 subcutaneous injection was administrated in the penis.Results. Whereas relaxation induced by SNP was not affected by PnTx2-6, EFS-induced relaxation was significantly potentiated by this toxin as well as PnTx2-6 plus SNP. This potentiating effect was further increased by sildenafil, not altered by atropine, however was completely blocked by the N-type Ca2+ channels. High concentrated levels of radiolabeled PnTx2-6 was specifically found in the cavernosum tissue, suggesting PnTx2-6 is an important toxin responsible for P. nigriventer spider accident-induced priapism.Conclusion. We show that PnTx2-6 slows Na+ channels inactivation in nitrergic neurons, allowing Ca2+ influx to facilitate NO/cGMP signalling, which promotes increased NO production. In addition, this relaxation effect is independent of phosphodiesterase enzyme type 5 inhibition. Our data displays PnTx2-6 as possible pharmacological tool to study alternative treatments for erectile dysfunction.

KW - Corpus Cavernosum

KW - Erectile Physiology

KW - Nitric Oxide

KW - PnTx2-6 Toxin

KW - Relaxation

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