EFFECT OF ALPHA(1)-ADRENOCEPTOR ANTAGONISTS ON PROSTATIC PRESSURE AND BLOOD-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 effects in vivo using the anesthetized dog in an attempt to elucidate the predominant alpha1 adrenoceptor subtype mediating contractile responses of the canine prostate. Methods. The affinity of compounds for alpha, adrenoceptor subtypes was determined by displacement of [H-3] prazosin binding from stably transfected rat 1 fibroblasts expressing alpha1A, alpha1B, and alpha1C, adrenoceptor subtypes. The potency of these agents was then assessed in vivo using an anesthetized dog model allowing simultaneous measurement of prostatic pressure and blood pressure following 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) over alpha1B (pKi = 7.2) and alpha1A (pKi = 8.1). Doxazosin, terazosin, alfuzosin, and tamsulosin were potent antagonists of phenylephrine responses and in vivo derived ''pseudo pA2'' determinations showed that the drugs did not discriminate between prostatic and vascular receptors. 5-Methyl-urapidil was also a potent antagonist of phenylephrine-induced responses but was selective for prostatic pressure (''pseudo pA2'' = 8.7) over blood pressure (''pseudo pA2'' = 7.2). Conclusions. Data in the present study suggest a predominant role of the alpha1C adrenoceptor subtype in the contractile response of the canine prostate to phenylephrine in vivo. This model therefore provides a suitable means of assessing putative prostate-selective antagonists for the treatment of benign prostatic hyperplasia.