silodosin and Ureteral-Obstruction

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adrenergic alpha-1 Receptor Antagonists; Animals; Blood Flow Velocity; Deoxyguanosine; Disease Models, Animal; Female; Immunohistochemistry; In Situ Hybridization; Indoles; Laser-Doppler Flowmetry; Microcirculation; Nerve Growth Factor; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Regional Blood Flow; Time Factors; Ureteral Obstruction; Urinary Bladder; Urinary Bladder Neck Obstruction; Urination; Urodynamics; Urological Agents

α1 -adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the α1 A -AR selective antagonist silodosin (compared to tamsulosin and prazosin) on ureter pressures in a rat model of ureter obstruction, and on contractions of human and rat isolated ureters.. After ethical approval, ureters of male rats were cannulated beneath the kidney pelvis for in vivo ureteral intraluminal recording of autonomous peristaltic pressure waves. A partial ureter obstruction was applied to the distal ureter. Mean arterial blood pressure (MAP) was recorded. Approximate clinical and triple clinical doses of the α1 -AR antagonists were given intravenously. Effects by the α1 -AR antagonists on isolated human and rat ureters were studied in organ baths.. Intravenous silodosin (0.1-0.3 mg kg(-1) ) or prazosin (0.03-0.1 mg kg(-1) ) reduced obstruction-induced increases in intraluminal ureter pressures by 21-37% or 18-40% respectively. Corresponding effects by tamsulosin (0.01 or 0.03 mg kg(-1) ) were 9-20%. Silodosin, prazosin and tamsulosin reduced MAP by 10-12%, 25-26% (P < 0.05), or 18-25% (P < 0.05) respectively. When effects by the α1 A -AR antagonists on obstruction-induced ureter pressures were expressed as a function of MAP, silodosin had six- to eightfold and 2.5- to eightfold better efficacy than tamsulosin or prazosin respectively. Silodosin effectively reduced contractions of both human and rat isolated ureters.. Silodosin inhibits contractions of the rat and human isolated ureters and has excellent functional selectivity in vivo to relieve pressure-load of the rat obstructed ureter. Silodosin as pharmacological ureter stone expulsive therapy should be clinically further explored.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Arterial Pressure; Dose-Response Relationship, Drug; Humans; Indoles; Male; Muscle Contraction; Prazosin; Rats; Rats, Sprague-Dawley; Species Specificity; Sulfonamides; Tamsulosin; Ureter; Ureteral Obstruction