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Sympathetic hypoactivity leads to hypocontractility of the corpus cavernosum in sickle cell mice: a mechanism contributing to priapism

International Journal of Impotence Research (2024)Cite this article

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Abstract

Priapism, a prevalent complication in sickle cell disease (SCD) patients, manifests as prolonged and painful erections unrelated to sexual arousal. The detailed mechanisms contributing to this condition, especially regarding sympathetic function in the corpus cavernosum that maintains penile flaccidity, remain to be elucidated. In this study, it was hypothesized that the pathways of the sympathetic nervous system would be down-regulated, thereby contributing to the development of ischemic priapism in sickle cell disease. This study aimed to investigate the contractions induced by stimulation of sympathetic terminals and the expression of tyrosine hydroxylase in the corpora cavernosa of Berkeley SCD mice. C57BL/6 mice (wild-type, WT) and Berkeley SCD mice were used. A total of 22 mice were used in this study, with 11 allocated to the WT group and 11 to the SCD group. Mice corpus cavernosum was dissected free and mounted in 7-mL organ baths containing Krebs solution. Noradrenergic contractions were obtained using electrical-field stimulation (4–32 Hz) in corpus cavernosum strips from WT and SCD mice. Measurements of tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured by western blot. The neurogenic contractions were significantly lower (P < 0.05) in the SCD group compared to WT group at all tested frequencies. The protein expression of both total tyrosine hydroxylase and tyrosine hydroxylase phosphorylated at Ser-31 was significantly decreased by approximately 46.28% (P = 0.01) and 55.32% (P = 0.03) in cavernosal tissues from the SCD group compared to the control group, respectively. In conclusion, sympathetic hypoactivity characterized by the downregulation of tyrosine hydroxylase contributes to the hypocontractility of the corpus cavernosum in Berkeley SCD mice. This suggests an impairment in the mechanism responsible for maintaining penile flaccidity, potentially predisposing to erections without sexual stimulation, similar to those observed in ischemic priapism. Pharmacological treatments aiming to restore sympathetic tone in the penis might hold promise for addressing ischemic priapism in SCD.

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Fig. 1: Frequency-dependent contractions induced by EFS in corpus cavernosum smooth muscle of control and SCD mice.
Fig. 2: Protein expression of total TH and TH phosphorylated at Ser-31 in cavernosal tissue of SCD mice.
Fig. 3: The hypocontractility of the corpora cavernosa smooth muscle cells is due to the downregulation of tyrosine hydroxylase (TH) expression.

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Data availability

The data supporting this study’s findings are available from the corresponding author

upon reasonable request.

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Funding

This work was supported by São Paulo Research Foundation (Grant Number: 2017/08122-9 and 2019/18886-1).

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Authors and Affiliations

  1. Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil

    Tammyris Helena Rebecchi Silveira, Dalila Andrade Pereira & Fábio Henrique Silva

  2. Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil

    Fabiano Beraldi Calmasini

  3. Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil

    Fernando Ferreira Costa

  4. The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Arthur L. Burnett

Authors
  1. Tammyris Helena Rebecchi Silveira
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  6. Fábio Henrique Silva
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Contributions

FHS designed the study with input ALB, FBC and FFC. DAP and THRS performed the experiments and collected and contributed data to the study. FFC provided the infrastructure for the data. All authors analyzed the data. FHS and THRS wrote the first draft of the manuscript. ALB, FFC and FHS drafted the manuscript. All authors discussed the results and contributed to the final paper.

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Correspondence to Fábio Henrique Silva.

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The authors declare no competing interests.

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All experimental procedures were performed in accordance with the relevant guidelines and regulations. The study was approved by the Ethics Committee on Animal Use of the University of Campinas (CEUA/UNICAMP), under permit number 4754-1/2017. Consent to participate is not applicable.

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Silveira, T.H.R., Pereira, D.A., Calmasini, F.B. et al. Sympathetic hypoactivity leads to hypocontractility of the corpus cavernosum in sickle cell mice: a mechanism contributing to priapism. Int J Impot Res (2024). https://doi.org/10.1038/s41443-024-00997-1

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