BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.
Authors: Kiriaki K Stamatelou; Mildred E Francis; Camille A Jones; Leroy M Nyberg; Gary C Curhan Journal: Kidney Int Date: 2003-05 Impact factor: 10.612