COMPARATIVE ALPHA-1-ADRENOCEPTOR SUBTYPE SELECTIVITY AND FUNCTIONAL UROSELECTIVITY OF ALPHA-1-ADRENOCEPTOR ANTAGONISTS

We investigated the relevance of selectivity for a given alpha-1-adren oceptor subtype for in vivo uroselectivity of several alpha-1-adrenoce ptor antagonists (alfuzosin, doxazosin, prazosin, tamsulosin, terazosi n and 5-Me-urapidil). Comparison of the affinities of these alpha-1-ad renoceptor antagonists at the cloned alpha-1a, alpha-1b and alpha-1d-a drenoceptor subtypes revealed that tamsulosin and 5-Me-urapidil showed selectivity for the alpha-1a subtype. No significant correlations wer e found between the affinities for alpha-1b or alpha-1d-adrenoceptors and the pK(B) values obtained against phenylephrine-induced contractio n of the rabbit prostate in vitro. In contrast, the antagonist potenci es in rabbit prostate were correlated (r = 0.89, P<.05) with the pK(i) values for the alpha-1a-adrenoceptor subtype. However, the pK(B) valu es were consistently smaller (by 0.6 to 1.9 log unit) than the pK(i) v alues for the alpha-1a-adrenoceptor subtype, a result that suggests th at the alpha-1-adrenoceptor mediating urethral contractions does not h ave all the characteristics of the alpha-1a-adrenoceptor. The simultan eous measurement of urethral and arterial pressures in the same consci ous male rat allows evaluation of the functional uroselectivity of the se antagonists based on their respective effects on both pressures. Do se ranges were selected according to effects on urethral pressure and most antagonists were found effective within the 3 to 100 mu g/kg i.v. range. Alfuzosin markedly decreased urethral pressure and either did not decrease blood pressure (10-30 mu g/kg) or slightly decreased it a t the highest dose tested (100 mu g/kg). Doxazosin did not produce sus tained reductions in urethral pressure until a dose of 30 mu g/kg. Blo od pressure was not reduced until 100 mu g/kg. Prazosin reduced urethr al pressure and blood pressure within the same dose-range whereas tera zosin did not decrease urethral pressure at doses that significantly d ecreased blood pressure (30 and 100 mu g/kg). 5-Me-urapidil, an alpha- 1a-selective compound did not significantly modify urethral and blood pressure whereas tamsulosin, another alpha-1a-selective compound reduc ed urethral pressure and blood pressure within the same dose range. In conclusion, in the conscious male rat the functional uroselectivity i s not correlated with a selective affinity for the alpha-1a-adrenocept or subtype.