Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2020-03, Vol.318 (3), p.F754-F762
• Main Authors: Alexandre, Eduardo C, Cao, Nailong, Mizoguchi, Shinsuke, Saito, Tetsuichi, Kurobe, Masahiro, Gotoh, Daisuke, Okorie, Meri, Igarashi, Taro, Antunes, Edson, Yoshimura, Naoki
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Animal tissues; Animals; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium ions; Change detection; Contraction; Cyclic GMP; Cytochrome; Cytochrome-c oxidase; Cytochromes; Cytokines; Cytokines - genetics; Cytokines - metabolism; Formaldehyde - toxicity; Gene expression; Gene Expression Regulation - drug effects; Growth factors; Guanylate cyclase; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factors; Inflammation; Inflammation - chemically induced; Inflammation - metabolism; Inositol 1,4,5-trisphosphate receptors; Interleukins; Kinases; Male; Multidrug resistance; Multidrug Resistance-Associated Proteins; Nitric oxide; Nitric-oxide synthase; Oxidase; Phenylephrine; Phosphodiesterase; Prostate; Prostate - drug effects; Prostate - pathology; Prostatitis - chemically induced; Protein kinase; Protein kinase C; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Signs and symptoms; Sodium nitroprusside; Urethral Diseases - etiology; Urinary tract
• ISSN: 1931-857X; 0363-6119; 1522-1466; 1522-1490
• DOI: 10.1152/ajprenal.00566.2019

Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome oxidase subunit 2, transforming growth factor-β , interleukin-1β, hypoxia-inducible factor-1α, α -adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca channel subunit-α , neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase subunit 2, transforming growth factor-β , interleukin-1β, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.