Mechanism of alpha-blockers as expulsive therapy probed

August 1, 2005

San Antonio--Using their established ex vivo model for measuring ureteral contractility, urologists at the University of Wisconsin, Madison have demonstrated that the nonselective alpha-1 receptor antagonist doxazosin (Cardura) relaxes ureteral smooth muscle and reverses the contractile effects induced by phenylephrine and epinephrine.

"There have been recent reports describing improved stone passage rates in patients with distal ureteral stones treated with the selective alpha-1 adrenergic receptor antagonist tamsulosin [Flomax]. The results of our study using doxazosin suggest the mechanism of action for stone passage may involve reversal of the contractile effect of epinephrine on ureteral smooth muscle," said Stephen Y. Nakada, MD, principal investigator and chairman of urology at the University of Wisconsin.

In the ex vivo model, 4-to 5-mm segments of porcine ureter were suspended in organ tissue baths containing Krebs buffer and were attached to forced displacement transducers. Contractility rates then were recorded with a polygraph.

The experiments were repeated, with the untreated or doxazosin-treated tissues ex-posed to a concentration-response curve of epinephrine in log10 incremental concentrations over the range from 1 nM to 10 micromolar. For each experimental condition, measurements were obtained using groups of eight segments for the control tests and four segments for the pharmacologic tests.

Dose-dependent response

The results showed that, for all portions of the porcine ureter, doxazosin acted in a dose-response fashion to reduce spontaneous contractility and reverse epinephrine-and phenylephrine-induced contractility. There were no significant differences in contractility rates observed among different locations within the ureter. The effect of doxazosin for inhibiting contractility was weakest in the untreated control segments and strongest for reversing epinephrine-induced contractility, Dr. Nakada reported.

"The potent effect of doxazosin for relaxing epinephrine-stimulated tissue is particularly interesting, considering that epinephrine-induced contractility is likely the circumstance that is present clinically in cases of acute obstruction," he said.

With data pooled for all segments, spontaneous ureteral contractility was reduced 28% by 0.1 micromolar of doxazosin, 34% by 1 micromolar, and 44% by 10 micromolar. Epinephrine alone increased contractility by 440%, but when added to doxazosin-treated tissues, it caused relaxation. Contractions were completely inhibited when epinephrine, 100 nM, was added in the presence of doxazosin, 1 or 10 micromolar.

Dr. Nakada and urology research assistant Travis Jerde also used immunoblot analysis techniques to assess the expression of alpha-1 receptor subpopulations in the distal ureter. Samples of normal ureter were obtained from volunteers undergoing elective donor nephrectomy, and chronically obstructed tissue was obtained from patients undergoing nephrectomy to remove nonfunctioning kidneys. Both the normal and chronically obstructed distal ureteral segments were found to express alpha-1A, -1B, and -1D receptors.

Clinical application

"Results from clinical studies evaluating nonselective alpha-blockers and alpha-1D blockers as medical expulsive therapy are pending. We will now repeat our contractility studies using different alpha-blockers to understand their effect throughout the ureter." Dr. Nakada said.

He noted that reports of the efficacy of tamsulosin for facilitating stone passage and findings from the present study might raise the question of whether there is sufficient evidence-based rationale for using alpha-blockers as medical expulsive therapy.

"However, further investigations should be performed to confirm our proposed hypothesis for alpha-antagonist activity and to compare various alpha-antagonists so as to determine which agent is best suited to medical expulsive therapy and which stones can be treated in this way," he added.