Vol. 292, Issue 3, 974-981, March 2000

Effects of Intracavernous Administration of Selective Antagonists of ₁-Adrenoceptor Subtypes on Erection in Anesthetized Rats and Dogs

Giorgio Sironi, Davide Colombo, Elena Poggesi, Amedeo Leonardi, Rodolfo Testa, Olivier Rampin¹, Jacques Bernabé¹ and Francois Giuliano²

Pharmaceutical R&D Division, Recordati S.p.A., Milan, Italy

The proerectile properties of three novel ₁-adrenoceptor (₁-ADR) antagonists with different profiles of selectivity for the ₁-ADR subtypes have been evaluated in anesthetized rats and dogs on intracavernous (IC) injection, in comparison with prazosin and phentolamine. In rats, the tested compounds decreased blood pressure (BP) and increased IC pressure (ICP), as well as the ratio ICP/BP. Rec 15/2841 (_1a- plus _1L-ADR-selective antagonist) and Rec 15/2615 (_1b-ADR selective) were the most potent compounds. The ICP/BP ratios calculated after injection of Rec 15/3039 (_1d-ADR selective) were not markedly different from those observed after vehicle injection. Prazosin and phentolamine proved poorly active, their main effect being hypotension. Approximate ED₂₅ values (dose of compound in micrograms inducing 25% increase of ICP/BP ratio) were Rec 15/2615 (22 µg/kg) >= Rec 15/2841 (29 µg/kg) > prazosin (136 µg/kg) > phentolamine (1298 µg/kg) > Rec 15/3039 (9600 µg/kg). Submaximal stimulation of the cavernous nerve elicited an ICP rise whose amplitude was not altered by Rec compounds. In contrast, prazosin and phentolamine decreased this ICP rise. All compounds but 15/3039 induced significant increase of the ICP/BP ratio in dogs. Rec 15/2615 proved to be the most interesting compound, inducing significant increases of ICP/BP at doses practically devoid of effects on BP. The rank order of potency in dog in increasing the ICP/BP ratio was similar to that observed in rats. Only at the highest doses tested, all compounds, except Rec 15/3039, decreased the ICP rise elicited by submaximal stimulation of the cavernous nerve. Our data demonstrate that the _1b- and _1L-ADR subtypes are functionally relevant for the erectile function in these models, and that _1b- and/or _1L-ADR subtypes selective antagonists could represent a real advantage in erectile dysfunction therapy.