Phatophysiological alterations in prostate from middle-aged rats

Author(s)

Fabiano Beraldi Calmasini

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2016-04-26

Examining board members

Edson Antunes; Fernando Silva Carneiro; Maria Andréia Delbin; Ricardo Miyaoka; Sérgio Luis Felisbino

• Advisor: Edson Antunes

Abstract

The increase in elderly population is becoming a worldwide phenomenon. Projections indicate that Brazil will be the sixth country in number of elderly people in 2020, exceeding 30 million people. Recent clinical studies suggest a strong relationship between aging and genitourinary tract diseases, being the benign prostatic hyperplasia (BPH) the most prevalent disease in men. Experimental studies also show a direct relationship between aging and prostatic changes. However, most of the studies have aimed to evaluate the prostate dysfunctions in elderly, neglecting the beginning of the changes in middle-aged. Thus, this study aimed to characterize the pathophysiological changes in the prostate of middle-aged rats. For this, young (3.5 months) and middle-age rats (10 months) were used. We first characterized the functional, biochemical and molecular changes in the prostate of middle-aged rats. We showed that intravenous administration of noradrenaline (10-7 to 10-4 g/kg) produced prostate smooth mucle (PSM) contractions in control and middle-aged group. Likewise, phenylephrine and ?,?-methylene ATP produced in vitro PSM concentration-dependent contractions that were higher in middle-aged rats. Likewise, electrical field stimulation (EFS 1-32 Hz) and [3H]-noradrenaline release induced by EFS were significantly higher in prostate of middle-age compared with control group. The relaxation induced by sodium nitroprusside (SNP, 1 nM - 10 mM) and the expression of the ?1 and ?1 subunits of sGC were reduced in middle-aged group. Moreover, the isoproterenol-induced relaxation (100 ?M - 10 uM) and cAMP production were also decreased in middle-aged group. The aging process lead to morphological changes in the prostate, characterized by an increase in the lumen and the smooth muscle cells, without affecting the epithelium and stroma. No difference was observed in production of prostatic reactive oxygen species production between the groups. Systemically, middle-aged rats showed insulin resistance and reduction in serum testosterone levels. In the second part of this study, we evaluated different pathways and pharmacological treatments involved in prostate hypercontractility in middle-aged animals. The relaxation induced by the selective rho-kinase inhibitor Y-27632 (1 nM - 100 uM) was lower in prostate from middle-aged animals. The in vitro rho-kinase inhibition by fasudil (10 µM) or chronic treatment (50 mg/kg/day, 2 weeks, intraperitoneal) was able to reverse the hypercontractility induced by EFS and phenylephrine in middle-aged animals. Likewise, chronic treatment with the ?3-adrenoceptor agonist mirabegron (20 mg/kg/day, 2 weeks, gavage) restored the PSM contraction in middle-aged animals without augmenting the cAMP levels. The in vitro PKC inhibition with GF109203X (1 µM), chronic treatment with apocynin (NADPH oxidase inhibitor), metformin (oral antihyperglicemic), and testosterone replacement were not able to normalize the prostatic changes in middle-age group. Thus, middle-aging leads to PSM hypercontractility accompanied with structural changes characterized by increase in lumen and smooth muscle, beside reduction in cAMP levels and sGC expression. The treatment with rho-kinase inhibitors and ?3-adrenoceptor agonists may be valuable pharmacological approaches to treating prostatic hypercontractility in middle age (AU)

• FAPESP's process: 14/02195-6 - Functional and molecular alterations of prostatic smooth muscle by aging in rats: role of oxidation and degradation of soluble guanylyl ciclase
• Grantee: Fabiano Beraldi Calmasini
• Support Opportunities: Scholarships in Brazil - Doctorate