Aging impairs urethral function in male rats: Increased outlet resistance and oxidative stress

Epidemiological studies identify age as the primary unmodifiable risk factor for male lower urinary tract symptoms (LUTS). While research has focused on the bladder and prostate, the urethra remains understudied. This study investigates aging-induced changes in rat urethral structure and function and their impact on voiding. Male Wistar rats, young (3.5 months) and middle-aged (10 months), were used. Cystometry assessed voiding in vivo, and isolated urethras were used in vitro. Middle-aged rats showed irregular micturition with increased basal pressure, bladder capacity, compliance, and non-voiding contractions, suggesting elevated outlet resistance. Histology showed no significant differences. Contractions to electrical-field stimulation and the α1-adrenoceptor agonist phenylephrine were enhanced, along with a twofold increase in α1A-adrenoceptor mRNA. Conversely, relaxation to nitric oxide (NO) donors sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) was reduced, while responses to the cGMP analog 8Br-cGMP and the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 were unchanged. Lower NO levels, despite increased endothelial NO synthase (eNOS) mRNA, were observed in middle-aged urethras, with no changes in neuronal NOS (nNOS) or sGC subunit β1. Phosphodiesterase type 5 (PDE5) mRNA was elevated, correlating with reduced basal and SNP-stimulated cGMP. Oxidative stress was evident, with increased superoxide and reduced expression of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). NADPH oxidase 2 (NOX2) and xanthine dehydrogenase (XDH) mRNA were upregulated, while hypoxia-inducible factor 1-alpha (HIF1α) remained unchanged. In summary, middle-aged rats show urethral hypercontractility, impaired relaxation, and oxidative stress, without tissue remodeling or ischemia.