FUNCTIONAL ANTAGONISTIC ACTIVITY OF REC-15 2739, A NOVEL ALPHA-1 ANTAGONIST SELECTIVE FOR THE LOWER URINARY-TRACT, ON NORADRENALINE-INDUCEDCONTRACTION OF HUMAN PROSTATE AND MESENTERIC-ARTERY/

The aim of this study was to compare with known reference standards th e functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline-induced contractions of human prostate and mesenteric ar tery. We also characterized these tissues with regard to the alpha-1 a drenoceptor subtypes present. Comparing the apparent pK(B) values reve aled Rec 15/2739 to be one of the most potent compounds acting on the prostate. Its potency was slightly lower than that of tamsulosin and w as higher than the potencies of prazosin, terazosin and 5-methylurapid il. On the mesenteric artery, tamsulosin was the most potent compound. Comparing the results from the functional studies with those obtained from radioreceptor binding studies, we found that the potency (pK(B) value) in inhibiting the contraction of prostatic tissue showed a clos e and significant correlation with the affinity for native and recombi nant alpha-1A adrenoceptors. No significant correlation was found with affinity for either the native or the recombinant alpha-1B adrenocept or subtype, or for recombinant alpha-1d receptors. Similar results wer e obtained for mesenteric artery. In order to characterize further the alpha-1 adrenoceptor subtypes present in the examined tissues, we inv estigated the functional effects of chloroethylclonidine, an alpha-1B- D subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of nifedipine, which antagonizes the extracellular calcium infl ux primarily mediated by alpha-1A adrenoceptor stimulation. The result s indicate the presence of both chloroethylclonidine-sensitive and -in sensitive alpha-1 adrenoceptor subtypes in the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be present exclusi vely. The possibility that the functionally relevant alpha-1 adrenocep tor subtype could be classified as alpha-1 L in both tissues should al so be considered.