Abstract

We investigated the relevance of selectivity for a givenalpha-1-adrenoceptor subtype for in vivouroselectivity of several alpha-1-adrenoceptor antagonists (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin and 5-Me-urapidil). Comparison of the affinities of thesealpha-1-adrenoceptor antagonists at the clonedalpha-1a, alpha-1b andalpha-1d-adrenoceptor subtypes revealed that tamsulosin and 5-Me-urapidil showed selectivity for the alpha-1a subtype. No significant correlations were found between the affinities foralpha-1b or alpha-1d-adrenoceptors and thepK_B values obtained against phenylephrine-induced contraction of the rabbit prostate in vitro. In contrast, the antagonist potencies in rabbit prostate were correlated (r = 0.89, P < .05) with thepK_i values for thealpha-1a-adrenoceptor subtype. However, thepK_B values were consistently smaller (by 0.6 to 1.9 log unit) than the pK_i values for thealpha-1a-adrenoceptor subtype, a result that suggests that the alpha-1-adrenoceptor mediating urethral contractions does not have all the characteristics of thealpha-1a-adrenoceptor. The simultaneous measurement of urethral and arterial pressures in the same conscious male rat allows evaluation of the functional uroselectivity of these antagonists based on their respective effects on both pressures. Dose ranges were selected according to effects on urethral pressure and most antagonists were found effective within the 3 to 100 μg/kg i.v. range. Alfuzosin markedly decreased urethral pressure and either did not decrease blood pressure (10–30 μg/kg) or slightly decreased it at the highest dose tested (100 μg/kg). Doxazosin did not produce sustained reductions in urethral pressure until a dose of 30 μg/kg. Blood pressure was not reduced until 100 μg/kg. Prazosin reduced urethral pressure and blood pressure within the same dose-range whereas terazosin did not decrease urethral pressure at doses that significantly decreased blood pressure (30 and 100 μg/kg). 5-Me-urapidil, an alpha-1a-selective compound did not significantly modify urethral and blood pressure whereas tamsulosin, another alpha-1a-selective compound reduced urethral pressure and blood pressure within the same dose range. In conclusion, in the conscious male rat the functional uroselectivity is not correlated with a selective affinity for thealpha-1a-adrenoceptor subtype.