EFFECTS OF SELECTIVE AND NONSELECTIVE ALPHA-1-ADRENOCEPTOR ANTAGONISTS ON INTRAURETHRAL AND ARTERIAL PRESSURES IN INTACT CONSCIOUS DOGS

In this study, we used a novel conscious dog model to evaluate the uro selectivity of selected alpha(1)-antagonists either approved for human use or in clinical development for the treatment of symptomatic benig n prostatic hyperplasia (BPH) and compared those results to their in v itro binding and functional affinities at alpha(1A), alpha(1B) and alp ha(1D) receptor subtypes. Conscious dogs were instrumented acutely wit h a balloon catheter for the measurement of changes in prostatic intra urethral pressure (IUP) and chronically with implantable telemetry dev ices for the measurement of arterial pressure. The presser effects of the alpha(1)-agonist phenylephrine (PE) on IUP and mean arterial press ure (MAP) were compared before and at various time points after oral d oses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SE 216 469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; howe ver, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2 739 at each dose always blocked IUP to a greater extent than MAP. Whil e the in vivo uroselectivity of these agents was predicted by radiolig and binding and in vitro functional selectivity for the alpha(1A) subt ype over alpha(1B) and alpha(1D) subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also dep end upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of urose lectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practic e.