期刊
JOURNAL OF UROLOGY
卷 194, 期 5, 页码 1481-1490出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.juro.2015.06.081
关键词
penile erection; peptide; Tx2-6 protein; Phoneutria nigriventer; drug evaluation; preclinical; chemistry techniques; synthetic
资金
- INCTTOX
- CAPES
- FAPEMIG
- CNPq
- American Heart Association Grant [SDG 12SDG12080023]
- Fonds Wetenschappelijk Onderzoek Vlaanderen [G.0433.12, G.A071.10N]
- Inter-University Attraction Poles Program Grant from Belgian State, Belgian Science Policy [IUAP 7/10]
- KU Leuven [OT/12/081]
Purpose: We designed a peptide, PnPP-19, comprising the potential active core of the Phoneutria nigriventer native toxin PnTx2-6. We investigated its role on erectile function, and its toxicity and immunogenicity. Materials and Methods: Erectile function was evaluated by the intracavernous pressure-to-mean arterial pressure ratio during electrical field stimulation on rat pelvic ganglia. Cavernous strips were contracted with phenylephrine and relaxation was induced by electrical field stimulation with or without PnPP-19 (10(-8) M). Activity on sodium channels was evaluated by electrophysiological screening of transfected channels on Xenopus oocytes and dorsal root ganglion cells. Antibodies were detected by indirect enzyme-linked immunosorbent assay in mice previously treated with the peptide. Histopathological studies were performed with mouse organs treated with different doses of PnPP-19. Results: PnPP-19 was able to potentiate erection at 4 and 8 Hz in vivo and ex vivo. It showed no toxicity and low immunogenicity in mice, and did not affect sodium channels or rat hearts. PnPP-19 increased cyclic guanosine monophosphate levels at 8 Hz. This effect was inhibited by L-NAME (10(-4) M). Erectile function was partially inhibited by 7-nitroindazole (10(-5) M), a selective inhibitor of neuronal nitric oxide synthase. Conclusions: PnPP-19 potentiates erection in vivo and ex vivo via the nitric oxide/cyclic guanosine monophosphate pathway. It does not affect sodium channels or rat hearts and shows no toxicity and low immunogenicity. These findings make it a promising candidate as a novel drug in the therapy of erectile dysfunction.
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