EFFECT OF ALPHA(1)-ADRENOCEPTOR ANTAGONISTS ON PROSTATIC PRESSURE ANDBLOOD-PRESSURE IN THE ANESTHETIZED DOG

Objectives. In the current study we have profiled a range of compounds at alpha1 adrenoceptor subtypes in vitro and have assessed their effe cts in vivo using the anesthetized dog in an attempt to elucidate the predominant alpha1 adrenoceptor subtype mediating contractile response s of the canine prostate. Methods. The affinity of compounds for alpha , adrenoceptor subtypes was determined by displacement of [H-3] prazos in binding from stably transfected rat 1 fibroblasts expressing alpha1 A, alpha1B, and alpha1C, adrenoceptor subtypes. The potency of these a gents was then assessed in vivo using an anesthetized dog model allowi ng simultaneous measurement of prostatic pressure and blood pressure f ollowing intravenous (i.v.) administration of phenylephrine (1 to 128 mug/kg). Results. All compounds examined in this study showed high and similar affinity for alpha1 adrenoceptor subtypes, with the exception of 5-Methyl-urapidil, which was selective for alpha1C (pKi = 9.3) ove r alpha1B (pKi = 7.2) and alpha1A (pKi = 8.1). Doxazosin, terazosin, a lfuzosin, and tamsulosin were potent antagonists of phenylephrine resp onses and in vivo derived ''pseudo pA2'' determinations showed that th e drugs did not discriminate between prostatic and vascular receptors. 5-Methyl-urapidil was also a potent antagonist of phenylephrine-induc ed responses but was selective for prostatic pressure (''pseudo pA2'' = 8.7) over blood pressure (''pseudo pA2'' = 7.2). Conclusions. Data i n the present study suggest a predominant role of the alpha1C adrenoce ptor subtype in the contractile response of the canine prostate to phe nylephrine in vivo. This model therefore provides a suitable means of assessing putative prostate-selective antagonists for the treatment of benign prostatic hyperplasia.